Fused pyridazine compounds

ABSTRACT

A fused pyridazine compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof which exhibits an inhibitory activity against cyclic GMP phosphodiesterase (hereinafter referred to as “cGMP-PDE”). 
     The compounds are useful as preventive and therapeutic agents for diseases for which a cGMP-PDE inhibiting action is efficacious, for example, ischemic heart diseases such as angina pectoris, myocardial infarct and chronic and acute cardiac failure, pulmonary hypertension, arteriosclerosis and bronchial asthma.

This application is a divisional of application Ser. No. 08/619,621,filed on Apr. 9, 1996 now U.S. Pat. No. 5,849,741. Application Ser. No.08/619,621 is the national phase of PCT International Application No.PCT/JP95/01575 filed on Aug. 8, 1995 under 35 U.S.C. § 371. The entirecontents of each of the above identified applications are herebyincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to a novel fused pyridazine compound. Inparticular, the present invention relates to a novel fused pyridazinecompound which is useful as drug.

DESCRIPTION OF RELATED BACKGROUND ART

Recently, studies on compounds exhibiting inhibitory activity againstcyclic GMP phosphodiesterase (hereinafter referred to as “cGMP-PDE”)have proceeded and attempts have been made to apply such compounds tothe prevention and treatment of circulatory failures such ashypertension, angina pectoris and myocardial infarct.

Known examples of the compound usable in the prevention and treatment ofcirculatory failures include quinazoline compounds disclosed inJP-A-29582/1975, 4H-3,1-benzoxazin-4-one compounds disclosed in WO88/09790, 1H-2,3,4,5-tetra-hydroimidazo[2,1-b)quinazolin-2-one and1,2,3,4,5,6-hexahydropyrimido[2,1-b]quinazolin-2-one disclosed inJP-A-86894/1973, nitrogenous heterocyclic compounds disclosed in WO93/07124 and 4-aminoquinazoline derivatives disclosed in EP 579496.

However, most of the compounds described above are not on the market andmany of them have problems of solubility, in vivo dynamics and toxicitywhich must be solved prior to the use as drugs.

DISCLOSURE OF THE INVENTION

Under the above circumstances, the inventors of the present inventionhave started their studies for the purpose of finding a compound whichexhibits an excellent cGMP-PDE inhibiting activity, has such a highwater solubility as to be well absorbed into the living body, and isless toxic.

As a result of the studies, they have found that the above object can beattained by a fused pyridazine compound represented by the followinggeneral formula (I) or a pharmacologically acceptable salt thereof. Thepresent invention has been accomplished on the basis of this finding.

{wherein ring C represents a five- or six-membered ring which maycontain a heteroatom;

n is an integer of 0 to 4;

R¹ represents a halogen atom, an optionally substituted lower alkylgroup, optionally substituted lower alkoxy group, an optionallysubstituted cycloalkyl group, a nitro group, a cyano group, —NR²R³(wherein R² and R³ represent each independently a hydrogen atom, anoptionally substituted lower alkyl group, an acyl group, optionallysubstituted arylalkyl group or an optionally substituted heteroarylalkylgroup, or alternatively R² and R³ together with the nitrogen atom towhich they are bonded may form a ring which may be substituted), —O—R⁹(wherein R⁹ represents a hydrogen atom, an optionally substituted loweralkyl group, an acyl group, an optionally substituted arylalkyl group oran optionally substituted heteroarylalkyl group), —S—R¹⁰ (wherein R¹⁰represents a hydrogen atom, an optionally substituted lower alkyl group,an acyl group, an optionally substituted arylalkyl group or anoptionally substituted heteroarylalkyl group),

(wherein R¹¹ represents a hydrogen atom, a lower alkyl group or an aminogroup; and m is an integer of 0 to 2), or an optionally protectedcarboxyl group, with the proviso that when n is 2 to 4, R¹'s representeach independently a substituent selected from among those describedabove;

A represents a hydrogen atom, a halogen atom, —NR⁴R⁵ (wherein R⁴ and R⁵represent each independently a hydrogen atom, an optionally substitutedlower alkyl group, an acyl group, an optionally substituted arylalkylgroup or an optionally substituted heteroarylalkyl group, oralternatively R⁴ and R⁵ together with the nitrogen atom to which theyare bonded may form a ring which may be substituted), an optionallysubstituted aryl group, an optionally substituted heteroaryl group, anoptionally substituted arylalkyl group or an optionally substitutedheteroarylalkyl group;

X represents —NR⁶— (wherein R⁶ represents a hydrogen atom, an optionallysubstituted lower alkyl group, an optionally substituted arylalkyl groupor an optionally substituted heteroarylalkyl group) or —N═;

Y represents —CO— or —CB═ (wherein B represents a hydrogen atom, ahalogen atom, —NR⁷R⁸ (wherein R⁷ and R⁸ represent each independently ahydrogen atom, an optionally substituted lower alkyl group, an acylgroup, an optionally substituted arylalkyl group or an optionallysubstituted heteroarylalkyl group, or alternatively R⁷ and R⁸ togetherwith the nitrogen atom to which they are bonded may form a ring whichmay be substituted), —O—R¹² (wherein R¹² represents a hydrogen atom, anoptionally substituted lower alkyl group, an acyl group, an optionallysubstituted arylalkyl group or an optionally substituted heteroarylalkylgroup), —S—R¹³ (wherein R¹³ represents a hydrogen atom, an optionallysubstituted lower alkyl group, an acyl group, an optionally substitutedarylalkyl group or an optionally substituted heteroarylalkyl group), anoptionally substituted aryl group, an optionally substituted heteroarylgroup, an optionally substituted arylalkyl group or an optionallysubstituted heteroarylalkyl group]; and the symbol {overscore(--------)}

represents a double bond or a single bond, with the proviso that thecases wherein C represents a benzene ring and n is 0) are excepted.}

In the above definition of the general formula (I), the lower alkylgroup constituting the optionally substituted lower alkyl as definedwith respect to R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² andR¹³ may be a linear or branched lower alkyl group having 1 to 6 carbonatoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl,isoamyl and n-hexyl. The substituent constituting it includes a hydroxylgroup, a nitro group, an amino group, a cyano group, acyl groups such asan acetyl group and a benzoyl group; lower alkoxy groups such as amethoxy group and an ethoxy group; halogen atoms such as a fluorineatom, a chlorine atom, a bromine atom and an iodine atom; and anoptionally protected carboxyl group. One or more of these substituentsmay be bonded to one or more carbon atoms of the lower alkyl group.

The lower alkoxy group constituting the optionally substituted loweralkoxy group as defined with respect to R¹ may be one derived from theabove lower alkyl group, and examples thereof include a methoxy group,an ethoxy group and a propoxy group.

The substituent constituting it includes a hydroxyl group, a nitrogroup, an amino group, a cyano group, acyl groups such as an acetylgroup and a benzoyl group; lower alkoxy groups such as a methoxy groupand an ethoxy group; halogen atoms such as a fluorine atom, a chlorineatom, a bromine atom and an iodine atom; and an optionally protectedcarboxyl group. One or more of these substituents may be bonded to oneor more carbon atoms of the lower alkoxy group.

The cycloalkyl group constituting the optionally substituted cycloalkylgroup as defined with respect to R¹ may be one having 3 to 8 carbonatoms, while the substituent constituting it includes a hydroxyl group,a nitro group, an amino group, a cyano group, an acyl groups such as anacetyl group and a benzoyl group; lower alkoxy groups such as a methoxygroup and an ethoxy group; halogen atoms such as a fluorine atom, achlorine atom, a bromine atom and an iodine atom; and an optionallyprotected carboxyl group. One or more of these substituents may bebonded to one or more carbon atoms of the cycloalkyl group.

The acyl group as defined with respect to R², R³, R⁴, R⁵, R⁷, R⁸, R⁹,R¹⁰, R¹² and R¹³ may be one derived from an aliphatic, aromatic or acylgroup derived from heterocyclic ring, and examples thereof include loweralkanoyl groups such as a formyl group, an acetyl group, a propionylgroup, a butyryl group, a valeryl group, an isovaleryl group and apivaloyl group; aroyl groups such as a benzoyl group, a toluoyl groupand a naphthoyl group; and heteroaroyl groups such as a furoyl group, anicotinoyl group and an isonicotinoyl group. In short, the group may beone derived from any carboxylic acid. Among these, a formyl group, anacetyl group and a benzoyl group are preferable.

The aryl group constituting the optionally substituted aryl as definedwith respect to A and B may be one derived from an aromatic ring, andexamples thereof include phenyl, 1-naphthyl, 2-naphthyl and anthracenyl.The substituent constituting it includes a hydroxyl group, a nitrogroup, an amino group, a cyano group, acyl groups such as an acetylgroup and a benzoyl group; a lower alkoxy group such as a methoxy groupand an ethoxy group; halogen atoms such as a fluorine atom, a chlorineatom, a bromine atom and an iodine atom; and an optionally protectedcarboxyl group.

The heteroaryl group constituting the optionally substitutedheteroarylalkyl group as defined with respect to A and B may be a mono-or poly-cyclic group having one or more heteroatoms selected from amongnitrogen, sulfur and oxygen atom. Examples thereof include pyridyl,pyrrolyl, imidazolyl, pyrazolyl, pyrazyl, pyrimidyl, pyridazyl, thienyl,pyranyl, isothiazolyl, isoxazolyl, furazanyl, benzothienyl, furyl,indolyl, indolizinyl, isoindolyl, benzothiazolyl, benzoimidazolyl andquinazolyl. The substituent constituting it includes a hydroxyl group, anitro group, an amino group, a cyano group, acyl groups such as anacetyl group and a benzoyl group; lower alkoxy groups such as a methoxygroup and an ethoxy group; halogen atoms such as a fluorine group, achlorine group, a bromine group and an iodine group; and an optionallyprotected carboxyl group.

As defined above, R⁷ and R⁸ together with the nitrogen atom to whichthey are bonded may form a ring which may be substituted, and examplesof the ring include piperidinyl, pyrrolidinyl and piperazinyl. Thesubstituent for the ring includes a hydroxyl group, an optionallysubstituted amino group, an aminoalkyl group, a nitro group, anitroalkyl group, a lower alkoxy group, a lower alkoxyalkyl group, ahydroxyalkyl group, an optionally protected carboxyl group and anoptionally protected carboxyalkyl group, among which a hydroxyl group, ahydroxymethyl group, a hydroxyethyl group, a carboxymethyl group and acarboxyethyl group are preferable.

The aryl group constituting the optionally substituted arylalkyl groupas defined with respect to R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹², R¹³and Y may be one derived from an aromatic ring, and examples thereofinclude phenyl, 1-naphthyl, 2-naphthyl and anthracenyl. The groupcorresponding to the “alkyl” moiety constituting it may be one derivedfrom the above lower alkyl group. The substituent constituting itincludes a hydroxyl group, a nitro group, an amino group, a cyano group,acyl groups such as an acetyl group and a benzoyl group; lower alkoxygroups such as a methoxy group and an ethoxy group; halogen atoms suchas a fluorine atom, a chlorine group, a bromine atom and an iodinegroup; and an optionally protected carboxyl group.

The heteroaryl group constituting the optionally substitutedheteroarylalkyl as defined with respect to R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹², R¹³ and Y may be a mono- or poly-cyclic group having oneor more heteroatoms selected from among a nitrogen atom, a sulfur atomand an oxygen atom, and examples thereof include pyridyl, pyrrolyl,imidazolyl, pyrazolyl, pyrazyl, pyrimidyl, pyridazyl, thienyl, pyranyl,isothiazolyl, isoxazolyl, furazanyl, benzothienyl, furyl, indolyl,indolizinyl, isoindolyl, benzothiazolyl, benzoimidazolyl and quinazolyl.The group corresponding to the “alkyl” moiety constituting it may be onederived from the above lower alkyl group. The substituent constitutingit includes a hydroxyl group, a nitro group, an amino group, a cyanogroup, acyl groups such as an acetyl group and a benzoyl group; loweralkoxy groups such as a methoxy group and an ethoxy group; halogen atomssuch as a fluorine atom, a chlorine atom, a bromine atom and an iodinegroup; and an optionally protected carboxyl group.

The halogen atom as defined with respect to R¹, R¹², R¹³ and R¹⁴includes a fluorine atom, a chlorine atom, a bromine atom and an iodineatom.

The pharmacologically acceptable salt according to the present inventionincludes inorganic acid salts such as hydrochloride, sulfate,hydrobromide and phosphate; and organic acid salts such as formate,acetate, trifluoroacetate, maleate, fumarate, tartrate,methanesulfonate, benzenesulfonate and toluenesulfonate.

Although several compounds according to the present invention formhydrates, it is needless to say that the hydrates fall within the scopeof the present invention.

Among the compounds of the present invention, fused pyridazine compoundsrepresented by the following general formula (II) and pharmacologicallyacceptable salts thereof are preferable:

{wherein R¹ represents a hydrogen atom, a halogen atom, an optionallysubstituted lower alkyl group, an optionally substituted lower alkoxygroup, an optionally substituted cycloalkyl group, a nitro group, acyano group, —NR²R³ (wherein R² and R³ represent each independently ahydrogen atom, an optionally substituted lower alkyl group, an acylgroup, an optionally substituted arylalkyl group or an optionallysubstituted heteroarylalkyl group, or alternatively R² and R³ togetherwith the nitrogen atom to which they are bonded may form a ring whichmay be substituted), —O—R⁹ (wherein R⁹ represents a hydrogen group, anoptionally substituted lower alkyl group, an acyl group, an optionallysubstituted arylalkyl group or an optionally substituted heteroarylalkylgroup), —S—R¹⁰ (wherein R¹⁰ represents a hydrogen atom, an optionallysubstituted lower alkyl group, an acyl group, an optionally substitutedarylalkyl group or an optionally substituted heteroarylalkyl group),

(wherein R¹¹ represents a hydrogen atom, a lower alkyl group or an aminogroup: and m is an integer of 0 to 2), or optionally protected carboxyl,with the proviso that when n is 2 to 4, R¹'s represent eachindependently a substituent selected from among those described above;

A represents a hydrogen atom, a halogen atom, —NR⁴R⁵ (wherein R⁴ and R⁵represent each independently a hydrogen atom, an optionally substitutedlower alkyl atom, an acyl group, an optionally substituted arylalkylgroup or an optionally substituted heteroarylalkyl group, oralternatively R⁴ and R⁵ together with the nitrogen atom to which theyare bonded may form a ring which may be substituted), an optionallysubstituted aryl group, an optionally substituted heteroaryl group, anoptionally substituted arylalkyl group or an optionally substitutedheteroarylalkyl group;

X represents —NR⁶— (wherein R⁶ represents a hydrogen atom, an optionallysubstituted lower alkyl group, an optionally substituted arylalkyl groupor an optionally substituted heteroaryl group) or —N═;

Y represents —CO— or —CB═ [wherein B represents a hydrogen group, ahalogen atom, —NR⁷R⁸ (wherein R⁷ and R⁸ represent each independently ahydrogen atom, an optionally substituted lower alkyl group, an acylgroup, an optionally substituted arylalkyl group or an optionallysubstituted heteroarylalkyl group, or alternatively R⁷ and R⁸ togetherwith the nitrogen atom to which they are bonded may form a ring whichmay be substituted), —O—R¹² (wherein R¹² represents a hydrogen atom, anoptionally substituted lower alkyl group, an acyl group, an optionallysubstituted arylalkyl group or an optionally substituted heteroarylalkylgroup), —S—R¹³ (wherein R¹³ represents a hydrogen atom, an optionallysubstituted lower alkyl group, an acyl group, an optionally substitutedarylalkyl group or an optionally substituted heteroarylalkyl group), anoptionally substituted aryl group, an optionally substituted heteroarylgroup, an optionally substituted arylalkyl group or an optionallysubstituted heteroarylalkyl group]; and the symbol {overscore(--------)}

represents a double bond or a single bond, with the proviso that thecases wherein ring C represents a benzene ring and n is 0 are excepted.

Among the above preferable compounds, fused pyridazine compoundsrepresented by the following general formula (III) and pharmacologicallyacceptable salts thereof are desirable:

[wherein R^(1a) represents a halogen atom, an optionally substitutedlower alkyl group, an optionally substituted lower alkoxy group, anoptionally substituted cycloalkyl group, a nitro group, a cyano group or—NR²R³ (wherein R² and R³ represent each independently a hydrogen atom,an optionally substituted lower alkyl group, an acyl group, anoptionally substituted arylalkyl group or an optionally substitutedheteroarylalkyl group, or alternatively R² and R³ together with thenitrogen atom to which they are bonded may form a ring which may besubstituted);

R¹ represents a hydrogen atom, a halogen atom, an optionally substitutedlower alkyl group, an optionally substituted lower alkoxy group, anoptionally substituted cycloalkyl group, a nitro group, a cyano group,—NR²R³ (wherein R² and R³ represent each independently a hydrogen ayom,an optionally substituted lower alkyl group, an acyl group, anoptionally substituted arylalkyl group or an optionally substitutedheteroarylalkyl group, or alternatively R² and R³ together with thenitrogen atom to which they are bonded may form a ring which may besubstituted), —O—R⁹ (wherein R⁹ represents a hydrogen atom, anoptionally substituted lower alkyl group, an acyl group, an optionallysubstituted arylalkyl group or an optionally substituted heteroarylalkylgroup), —S—R¹⁰ (wherein R¹⁰ represents a hydrogen atom, an optionallysubstituted lower alkyl group, an acyl group, an optionally substitutedarylalkyl group or an optionally substituted heteroarylalkyl group),

(wherein R¹¹ represents a hydrogen atom, a lower alkyl group or an aminogroup; and m is an integer of 0 to 2), or an optionally protectedcarboxyl group, with the proviso that when n is 2 to 4, R¹'s representeach independently a substituent selected from among those describedabove;

A represents a hydrogen atom, a halogen atom, —NR⁴R⁵ (wherein R⁴ and R⁵represent each independently a hydrogen atom, an optionally substitutedlower alkyl group, an acyl group, an optionally substituted arylalkylgroup or an optionally substituted heteroarylalkyl group, oralternatively R⁴ and R⁵ together with the nitrogen atom to which theyare bonded may form a ring which may be substituted), an optionallysubstituted aryl group, an optionally substituted heteroaryl group, anoptionally substituted arylalkyl group or an optionally substitutedheteroarylalkyl group; and

B represents a hydrogen atom, a halogen atom, —NR⁷R⁸ (wherein R⁷ and R⁸represent each independently a hydrogen atom, an optionally substitutedlower alkyl group, an acyl group, an optionally substituted arylalkylgroup or an optionally substituted heteroarylalkyl group, oralternatively R⁷ and R⁸ together with the nitrogen atom to which theyare bonded may form a ring which may be substituted), —O—R¹² (whereinR¹² represents a hydrogen atom, an optionally substituted lower alkylgroup, an acyl group, an optionally substituted arylalkyl group or anoptionally substituted heteroarylalkyl group), —S—R¹³ (wherein R¹³represents a hydrogen, an optionally substituted lower alkyl group, anacyl group, an optionally substituted arylalkyl group or an optionallysubstituted heteroarylalkyl group), an optionally substituted arylgroup, an optionally substituted heteroaryl group, an optionallysubstituted arylalkyl group or an optionally substituted heteroarylalkylgroup].

Further, fused pyridazine compounds represented by the following generalformula (V) and pharmacologically acceptable salts thereof are moredesirable:

(wherein R^(1a) represents a halogen atom, an optionally substitutedlower alkyl group, an optionally substituted lower alkoxy group, anoptionally substituted cycloalkyl group, a nitro group, a cyano group or—NR²R³ (wherein R² and R³ represent each independently a hydrogen atom,an optionally substituted lower alkyl group, an acyl group, anoptionally substituted arylalkyl group or an optionally substitutedheteroarylalkyl group, or alternatively R² and R³ together with thenitrogen atom to which they are bonded may form a ring which may besubstituted);

B represents a hydrogen atom, a halogen atom, —NR⁷R⁸ (wherein R⁷ and R⁸represent each independently a hydrogen atom, an optionally substitutedlower alkyl group, an acyl group, an optionally substituted arylalkylgroup or an optionally substituted heteroarylalkyl group, oralternatively R⁷ and R⁸ together with the nitrogen atom to which theyare bonded may form a ring which may be substituted), —O—R¹² (whereinR¹² represents a hydrogen atom, an optionally substituted lower alkylgroup, an acyl group, an optionally substituted arylalkyl group or anoptionally substituted heteroarylalkyl group), —S—R¹³ (wherein R¹³represents a hydrogen atom, an optionally substituted lower alkyl group,an acyl group, an optionally substituted arylalkyl group or anoptionally substituted heteroarylalkyl group), an optionally substitutedaryl group, an optionally substituted heteroaryl group, an optionallysubstituted arylalkyl group or an optionally substituted heteroarylalkylgroup; and

R¹², R¹³ and R¹⁴ represent each independently a hydrogen atom, a halogenatom, an optionally substituted lower alkyl group or an optionallysubstituted lower alkoxy group, or alternatively two of R¹², R¹³ and R¹⁴which are bonded to the carbon atoms adjacent to each other may beunited to form methylenedioxy or ethylenedioxy).

Furthermore, compounds represented by the following general formula (V′)are most desirable:

(wherein R^(1a) represents a halogen atom, a nitro group or a cyanogroup, preferably a cyano group; B desirably represents —NR⁷R⁸ (whereinR⁷ and R⁸ represent each independently a hydrogen atom, an optionallysubstituted lower alkyl group, an acyl group, an optionally substitutedarylalkyl group or an optionally substituted heteroarylalkyl group, oralternatively R⁷ and R⁸ together with the nitrogen atom to which theyare bonded may form a ring which may be substituted), more desirably—NR⁷R⁸ (wherein R⁷ and R⁸ together with the nitrogen atom to which theyare bonded form a ring which is preferably substituted with a hydroxylgroup, a carboxyl group, a hydroxyalkyl group, a carboxyalkyl group orthe like, still preferably at the position 4. It is most desirable thatthe substituent is a hydroxyl group or hydroxyalkyl group.

The compounds of the present invention can be readily prepared by knownprocesses or combinations of known processes. Several main processes forthe preparation of the compounds of the present invention will now bedescribed, though it is needless to say that the compounds of thepresent invention are not limited to those prepared by these processes.

Preparation process 1

A compound represented by the general formula (I) wherein A and B areeach a halogen atom can be prepared by the following process:

(wherein A′ and B′ represent each independently a halogen atom; and R¹and n are each as defined above)

Specifically, the above compound can be prepared by halogenating acorresponding 1,4-phthalazinedione derivative. This halogenation can beconducted in a conventional manner. Examples of the chlorinating agentusable in this case include phosphorus pentachloride, phosphorusoxychloride and mixture of both. Although the halogenation can beconducted without any solvent, any solvent inert to the halogenation maybe used. In some cases, the use of a tertiary amine such asdiisopropylethylamine or N,N-dimethylformamide gives better results. Thereaction temperature preferably ranges from about room temperature toabout 150° C.

Preparation process 2

A compound represented by the general formula (I) wherein ring Crepresents a benzene ring; A and B represent each independently ahalogen atom; R¹ represents a cyano group; and n is 1 can be preparedalso by the following process:

(wherein A′ and B′ are each as defined above)

(1st step)

In this step, the amino group of 4-amino-phthalimide is converted into acyano group. This conversion is preferably conducted by the Sandmeyerreaction, though it may be conducted by any conventional process.According to the Sandmeyer reaction, the conversion is conducted byconverting 4-aminophthalimide into a diazonium salt in a conventionalmanner and thereafter reacting the diazonium salt with a nucleophilicreagent such as copper salt to replace the diazonium group by a cyanogroup. Although commercially available copper cyanide may be used inthis reaction, better results can be attained by the use of the coppercyanide prepared from potassium cyanide and cuprous chloride just beforeuse.

(2nd step)

In this step, the phthalimide derivative prepared in the 1st step isconverted into a corresponding 1,4-phthalazinidione. This conversion canbe conducted according to the process described in Castle: “HETEROCYCLICCOMPOUNDS”, Vol.27.

(3rd step)

In this step, the 1,4-phthalazinedione prepared in the above 2nd step isprepared according to Preparation process 1.

Preparation process 3

A compound represented by the general formula (I) wherein ring Crepresents a benzene ring; A and B represent each independently ahalogen atom; R¹ represents a cyano group; and n is 1 can be preparedalso by the following process:

(wherein A′ and B′ are each as defined above)

(1st step)

In this step, 4-carbamoylphthalimide is prepared by reactingtrimellitoyl chloride with ammonia and dehydrating the obtained product.Specifically, this reaction is conducted by reacting trimellitoylchloride with aqueous ammonia either without any solvent or in a statedissolved in a solvent at a temperature ranging from about −15° C. toroom temperature. The solvent to be used in this case is preferablyacetone, dichloromethane, chloroform or ethyl acetate, though anyorganic solvent inert to the reaction may be used. The resultingreaction mixture is treated with an acid to give a mixture comprising2,4-dicarbamoylbenzoic acid and 2,5-dicarbamoylbenzoic acid. Thismixture is further treated in the absence or presence of a solvent for0.5 to 24 hours to give the objective compound. This treatment isconducted at room temperature to about 200° C. The solvent to be used inthis treatment is preferably N-methyl-2-pyrrolidinone, though anysolvent inert to the reaction may be used.

(2nd step)

In this step, the phthalimide derivative prepared in the above 1st stepis converted into a phthalazinedione in a conventional manner.

This conversion can be conducted by a conventional process such asreaction with hydrazine hydrate or the like. The reaction temperature ispreferably 0° C. to room temperature.

(3rd step)

In this step, the 6-carbamoyl-2,3-dihydro-1,4-phthalazinedione preparedin the 2nd step is converted into 6-cyano-1,4-dichlorophthalazinethrough dehydration and chlorination. The reagent useable in this caseincludes phosphorus oxychloride, thionyl chloride, phosphoruspentachloride and mixtures of two or more of them. The reactiontemperature may range from room temperature to the boiling point of thereagent and the reaction time is about 0.5 to 36 hours. In some cases,better results can be attained by the addition of N,N-dimethylformamideor a tertiary amine such as diisopropylethylamine.

Preparation process 4

A compound represented by the formula (I) wherein A represents —NR²R³(wherein R² and R³ represent each independently a hydrogen atom, anoptionally substituted lower alkyl group, an acyl group, an optionallysubstituted arylalkyl group or an optionally substituted heteroarylalkylgroup, or alternatively R² and R³ together with the nitrogen atom towhich they are bonded may form a ring which may be substituted) and Brepresents a halogen atom can be prepared by the following process:

(wherein A′ represents a halogen atom; and R¹, R², R³, X and Y are eachas defined above).

Specifically, the above compound is prepared through the conventionalsubstitution reaction. The solvent to be used in the reaction may be anyorganic one inert to the reaction, and preferable examples of thesolvent include alcohols such as isopropyl alcohol; ethers such astetrahydrofuran and 1,4-dioxane; dimethylformamide, dimethylacetamideand N-methyl-2-pyrrolidinone.

The reaction temperature may preferably range from about roomtemperature to the refluxing temperature of the solvent.

Better results can be attained by the addition of a salt such aspotassium carbonate, sodium carbonate or barium carbonate, or a tertiaryamine such as diisopropylethylamine or DBU. In particular, the additionof a tertiary amine such as diispropylethylamine or DBU can give thebest results.

After the completion of the reaction, the reaction mixture ispost-treated in a conventional manner and is freed from undesirableisomers by recrystallization or treatment with a column to give anobjective compound.

Preparation process 5

A compound represented by the general formula (I) can be prepared alsoby the following process:

(wherein R¹, A, B, A′, B′, X and n are each as defined above)

According to this process, the objective compound is prepared from thehalophthalazine derivative prepared by Preparation process 4 or the likethrough conventional replacement. The solvent to be used in this case ispreferably N-methyl-2-pyrrolidinone, though any solvent inert to thereaction may be used. The reactant B-H is used in excess based on thestarting halophthalazine derivative. In some cases, better results canbe attained by the addition of an organic base such asdiisopropylethylamine, a salt such as potassium carbonate, sodiumcarbonate or sodium hydrogencarbonate, or an acid such asp-toluenesulfonic acid. Further, still better results can be attained byusing hydrochloride of the compound B-H without the above additive.

The reaction temperature may be from about room temperature to theboiling point of the solvent, preferably 100° C. or above.

Preparation process 6

A compound represented by the general formula (I) wherein Y is —CO— canbe prepared by the following process:

(wherein R¹, A, B′, X and n are each as defined above).

According to this process, the objective compound is prepared byhydrolyzing a corresponding halophthalazine derivative in a conventionalmanner. Specifically, the compound can be prepared by heating thecorresponding halophthalazine derivative in an acidic or alkalinesolution. In some case, better results can be attained when thehalophthalazine derivative is stirred under heating at 100 to 200° C. inan organic solvent such as N-methyl-2-pyrrolidinone in the presence ofacetic acid for about 0.5 to 12 hours.

Pharmacological Experimental Examples will now be described toillustrate the effects of the present invention.

PHARMACOLOGICAL EXPERIMENTAL EXAMPLE Experimental Example 1 InhibitoryActivity Against cGMP-PDE Prepared From Swine Lung

1. Experimental method

The enzyme activity of the cGMP-PDE prepared from swine lung wasdetermined according to the method of Thompson et al. This determinationwas conducted in the presence of 1 mM EGTA by the use of 1 mM cGMP assubstrate. Each compound according to the present invention wasdissolved in DMSO and thereafter added to the reaction system todetermine the inhibitory activity of the compound. The finalconcentration of DMSO in the reaction solution was controlled to 5% orbelow.

The preparation of cGMP-PDE was conducted as follows.

Swine lung was minched, followed by the addition of five times (byvolume) as much buffer A (comprising Tris/HCl (20 mM), Mg acetate (2mM), 2-mercaptoethanol (10 mM), EGTA (0.1 mM) and PMSF (0.2 mM) andadjusted to pH7.4). The resulting mixture was homogenized andcentrifuged at 1000×g for 5 minutes. Ammonium sulfate was added to theobtained supernatant and the resulting mixture was centrifuged at20000×g for 45 minutes to collect a fraction precipitating between 30and 40% saturation with ammonium sulfate. This fraction was dialyzedagainst buffer A and passed through a column of DEAE-Toyopearl 650S (aproduct of Tosoh, Tokyo, Japan). The column was washed with buffer A andsubjected to gradient elution with 0.05 to 0.2 M NaClibuffer A tocollect a cGMP-PDE fraction.

This cGMP-PDE fraction was passed through Blue-Sepharose CL-6B (aproduct of Pharmacia, Uppsala, Sweden). The resulting column was washedwith buffer A containing cAMP (10 mM) and NaCl (0.5 M) and eluted withbuffer A containing cGMP (10 mM) and NaCl (0.5 M). The obtained fractionwas dialyzed, concentrated and stored.

2. Experimental results

The cGMP-PDE inhibitory activities of the compounds of the presentinvention as determined by the above method are given in Table 1.

cGMP-PDE inhibitory activity PAP lowering Ex. No. IC50(nM) activity 11.7 ≧3 4 0.18 — 6 0.015 10 7 1.2 1 8 0.03 10 9 0.70 10 10 0.01 10 110.11 — 17 ≦0.01 — 19 0.53  3-10 20 0.12 0.3-1   25 1.41 3 26 4.0 1 313.74 1 32 4.4 1 36 1.9 ≧1 37 1.8 ≦0.33 43 0.37 1 44 2.1 ≦0.33 49 1.88 151 0.052 — 52 0.10 10 56 12.6 ≧1 53 0.23 10 55 4.59 ≧1 60 20.4 1 67 0.320.33

Experimental Example 2 Pulmonary Arterial Pressure Lowering Activity onAnesthetized Thoracotomized Dog by Intravenous Administration

1. Experimental method

Male and female hybrid dogs having a weight of about 10 kg were operatedunder enflurane anesthesia with N₂O/O₂ as carrier. Each dog wasthoracotomized in the left fourth intercostal space and a pressuretransducer (MPC-500 mfd. by Miller) was inserted into the pulmonaryartery to determine the pulmonary arterial pressure (PAP). Thisexperiment was conducted with the mean PAP (mPAP) increased by about 10mmHg by lowering the pressure of oxygen fed by about 40% of the normalone. Each compound according to the present invention was dissolved inPolyethylene glycol 400 (a product of Wako Pure Chemical Industries,Ltd.) in a concentration of 1 mg/ml and, if necessary, further dilutedwith Polyethylene glycol 400. The resulting solution was intravenouslyadministered to the dog through a polyethylene catheter indwelling inthe femoral vein.

2. Experimental results

The PAP lowering activities of the compounds of the present invention asdetermined by the above method are given in Table 1 in terms of relativeratios to the activity of sodium1-[chloro-4-(3,4-methylenedioxybenzyl)aminoquinazolin-2-yl]piperidine-4-carboxylate.

Experimental Example 3 In Vitro Platelet Aggregation Inhibiting Activity

1. Experimental method

Blood specimens (10 ml) were collected from the forearm veins of normalmale volunteers (age: 30 to 40 years, weight: 60 to 75 kg) who had nottaken any drug for at least one week therebefore. In order to preventblood coagulation, a 3.8% sodium citrate solution (Citral, a product ofYamanouchi Pharmaceutical Co., Ltd.) was added to the blood in an amountof one tenth of the blood volume. The resulting blood was centrifuged atroom temperature (22-25° C.) at 700 rpm for 10 minutes to recover asupernatant as platelet rich plasma (PRP). A blood anticoagulantsolution (a product of Terumo Corporation) was added to the PRP in afinal concentration of 15 v/v%. The resulting mixture was centrifuged atroom temperature at 3000 rpm for 10 minutes to give a platelet pellet.This platelet pellet was suspended in physiological saline solutioncontaining 0.1% of EDTA and the resulting suspension was centrifugedagain to give another platelet pellet. This pellet was suspended inCa²⁺-free Tyrode's solution in a final concentration of about 40×10⁷/ml.

The platelet aggregation was determined according to the turbidimetricmethod of Born et al. with an aggregometer (PAM-8C mfd. by Mebanix).Each compound according to the present invention was dissolved in DMSOin a concentration of 50 mM, followed by serial dilution with Ca²⁺-freeTyrode's solution. The Ca²+-free Tyrode's solution was used also ascontrol.

A mixture comprising 25 ml of each of the dilutions of the compound ofthe present invention prepared above and 200 ml of the washed plateletprepared above was incubated, followed by the addition of 25 ml of aplatelet coagulant. The resulting mixture was observed for aggregation.The platelet coagulant used was 3 mg/ml collagen (a product ofHormon-Chemie), 0.3 mM U46619 (a product of Cayman Chemical) or 0.04U/ml thrombin (a product of Sigma).

The inhibitory activities of the compounds of the present invention wererepresented in terms of inhibitory ratios based on the aggregationintensity of control (the area of turbidity chart of the aggregometer).

2. Experimental results

The platelet aggregation inhibiting activities of the compounds of thepresent invention as determined by the above method are given in Table 2in terms of inhibitory concentrations (mM).

Coagulant Ex. No. collagen U46619 thrombin  4 11 5.6 18 20 21(dihydrochloride- free) 32 28 43 61 63 80 (hydrochloride) 56 55 37 61

It can be understood from the results of the above pharmacologicalexperiments that the compounds of the present invention exhibit cGMP-PDEinhibitory activity, platelet aggregation inhibiting activity andpulmonary arterial pressure lowering activity. Accordingly, thecompounds of the present invention are useful as preventive andtherapeutic agents for diseases for which cGMP-PDE inhibiting action,platelet aggregation inhibiting action or pulmonary arterial pressurelowering action is efficacious. Specific examples of such diseasesinclude ischemic heart diseases such as angina pectoris, myocardialinfarct and chronic and acute heart failures; pulmonary hypertensionaccompanied by pulmonary heart and that not accompanied thereby;thrombosis caused by trauma of vascular wall, arterial sclerosis,vasculitis and so forth; hypertension caused by arterial sclerosis andothers; brain circulatory disturbances such as peripheral circulationfailure and cerebral infarction; cerebral malfunction; and allergicdiseases such as bronchial asthma, atopic dermatitis and allergicrhinitis.

The compounds of the present invention have higher water solubilitiesthan those of the compounds of the prior art having similar activitiesand structures. Therefore, they are excellent in the migration into theliving body in oral administration, which is an advantage of thecompounds of the present invention.

Further, the compounds of the present invention are less toxic andhighly safe, thus being extremely useful as drugs.

The compound of the present invention may be orally or parenterallyadministered as a therapeutic or preventive agent for the abovediseases. Although the dose thereof is not particularly limited butvaries depending upon the symptom, age, sex and drug sensitivity ofpatient; the method, timing and interval of administration; theproperties and kind of preparation; the kind of active ingredient and soforth, the dose per adult a day is preferably about 0.1 to 1000 mg,which may be administered in one to several portions.

The compounds of the present invention can be converted intopharmaceutical preparations by the use of conventional carriersaccording to conventional processes.

More precisely, a solid preparation for oral administration according tothe present invention is prepared by adding a filler and, if necessary,a binder,disintegrator, lubricant, color, corrigent and/or antioxidantto an active ingredient and shaping the obtained mixture into a tablet,coated tablet, granule, power or capsule.

Examples of the filler include lactose, corn starch, sucrose, glucose,sorbitol, crystalline cellulose and silicon dioxide.

Examples of the binder include polyvinyl alcohol, polyvinyl ether,ethylcellulose, methylcellulose, acacia, tragacanth, gelatin, shellac,hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate,dextrin and pectin; and examples of the lubricant include magnesiumstearate, talc, polyethylene glycol, silica and hardened vegetable oils.

Examples of the color include those authorized as pharmaceuticaladditives. Those of the corrigent include cocoa powder, menthol,aromatic powder, mentha oil, borneol and powdered cinnamon bark; andthose of the antioxidant include those authorized as pharmaceuticaladditives such as ascorbic acid and α-tocopherol. Of course, the tabletand granule may be suitably coated with sugar, gelatin or the like, ifnecessary.

On the other hand, an injection according to the present invention isprepared by adding a pH modifier, buffer, suspending agent, solubilizingagent, stabilizer, tonicity agent, antioxidant and/or preservative to anactive ingredient and formulating the mixture into an injection forintravenous, subcutaneous or intramuscular administration by aconventional process. If necessary, the injection may be freeze-dried.

Examples of the suspending agent include methyl-cellulose, Polysorbate80, hydroxyethylcellulose, acacia, tragacanth powder,carboxymethylcellulose sodium and polyoxyethylene sorbitan monolaurate.

Further, examples of the solubilizing agent include polyoxyethylenehardened castor oil, Polysorbate 80, nicotinamide and polyoxyethylenesorbitan monolaurate.

Furthermore, examples of the stabilizer include sodium sulfite, sodiummetasulfite and ether; and those of the preservative include methylp-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresoland chlorocresol.

EXAMPLE

Examples will now be described to facilitate the understanding of thepresent invention, though it is needless to say that the presentinvention is not limited to them. These Examples are preceded byPreparative Examples for starting compounds. For the sake ofconvenience, some compounds of the present invention are described asPreparative Examples, which does not limit the present invention.

Preparative Example 1 4-Cyanophthalimide

4-Aminophthalimide (40.0 g) was suspended in 300 ml of water, followedby the addition of 57 ml of concentrated hydrochloric acid. The obtainedsuspension was stirred under cooling with ice. A solution of 20.6 g ofsodium nitrite in 69 ml of water was dropped into the above suspensionat a bulk temperature of 5° C. or below.

The obtained mixture was cooled to −20° C., followed by the addition of300 ml of toluene. The resulting mixture was adjusted to pH7 with sodiumhydrogencarbonate under vigorous stirring to form a diazonium salt.

Separately, a solution of 105.7 g of potassium cyanide in 206 ml ofwater was dropped into a suspension of 63.4 g of cuprous chloride in 250ml of water, while the suspension was vigorously stirred under coolingwith ice. The obtained mixture was further stirred under cooling withice for one hour, followed by the addition of 500 ml of ethyl acetate.The diazonium salt prepared above was added into the resulting mixturein several portions and the obtained mixture was stirred under coolingwith ice for one hour.

The resulting mixture was filtered through Celite to remove insolublesand the Celite was washed with an ethyl acetate/tetrahydrofuran mixture.The filtrates were together left standing to cause liquid-liquidseparation. The organic phase was washed with a saturated aqueoussolution of sodium hydrogen-carbonate, dilute hydrochloric acid and asaturated aqueous solution of common salt, dried over anhydrousmagnesium sulfate and freed from the solvent by vacuum distillation. Thetitle compound (41 g) was obtained as a reddish-brown solid.

M.p.: 237.0-238.0° C.

MASS: 173 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 8.00(1H, dd, J=7.5, 1.0 Hz), 8.29(1H, dd,J=7.5, 1.5 Hz), 8.36(1H, dd, J=1.5, 1.0 Hz), 11.73(1H, s)

Preparative Example 2 6-Cyano-2,3-dihydro-1,4-phthalazinedione

4-Cyanophthalimide (80 g) was suspended in 1000 ml of ethanol, followedby the addition of 25 ml of hydrazine monohydrate. The obtained mixturewas stirred at room temperature for 5 hours.

The resulting mixture was concentrated in a vacuum to about one-half itsoriginal volume, followed by the addition of 1000 ml of water. Theobtained mixture was acidified with dilute hydrochloric acid toprecipitate crystals, which were recovered by filtration to give 71 g ofthe title compound as a brown powder.

1H-NMR (400 MHz, DMSO-d6) δ: 8.19(1H, brs), 8.27(1H, dd, J=8.0, 1.0 Hz),8.48(1H, brs), 11.39(2H, brs)

Preparative Example 3 6-Cyano-1,4-dichlorophthalazine

6-Cyano-2,3-dihydro-1,4-phthalazinedione (69 g) was suspended in 400 mlof phosphorus oxychloride, followed by the addition of 75 ml ofdiisopropylethylamine. The obtained mixture was heated under reflux for40 minutes.

Excess phosphorus oxychloride was distilled away in a vacuum and theresidue was dissolved in methylene chloride. The obtained solution waspoured onto ice/water. The resulting mixture was filtered through Celiteto remove insolubles and the Celite was washed weith methylene chloride.The filtrates were together extracted with methylene chloride and theorganic phase was washed with a saturated aqueous solution of sodiumhydrogencarbonate, dilute hydrochloric acid and a saturated aqueoussolution of common salt, dried over anhydrous magnesium sulfate andfiltered through silica gel. The filtrate was distilled in a vacuum toremove the solvent. The title compound (66 g) was obtained as a palelyyellowish-orange solid.

1H-NMR (400 MHz, CDCl3) δ: 8.24(1H, dd, J=8.5, 1.5 Hz), 8.47(1H, dd,J=8.5, 1.0 Hz), 8.68(1H, dd, J=1.5, 1.0 Hz)

Preparative Example 4 4-Carbamoylphthalimide

A solution of 21.1 g (0.10 mol) of trimellitoyl chloride in 25 ml ofacetone was dropped into 200 ml of 29% aqueous ammonia, while theaqueous ammonia was stirred under cooling with ice. The resultingmixture was as such stirred for one hour, deaerated in a vacuum andacidified with concentrated hydrochloric acid under cooling with ice.The crystals thus precipitated were recovered by filtration, washed withwater and dried with hot air to give 18.5 g of a mixture of2,4-dicarbamoylbenzoic acid and 2,5-dicarbamoylbenzoic acid as a whitecrystal (yield: 89%).

This mixture (16.0 g, 0.077 mol) was suspended in 80 ml ofN-methyl-2-pyrrolidinone. The obtained suspension was stirred underheating at 150° C. for 3 hours and cooled by allowing to stand, followedby the addition of 200 ml of water. The crystals thus precipitated wererecovered by filtration, washed with water and dried with hot air. Thetitle compound (13.3 g) was obtained as a light brown crystal (yield:91%).

1H-NMR (400 MHz, DMSO-d6) δ: 7.70(1H, br s), 7.90(1H, dd, J=7.2, 1.2Hz), 8.28-8.31(2H, m), 8.32(1H, br s), 11.48(1H, br s)

Preparative Example 5 6-Carbamoyl-2,3-dihydro-1,4-phthalazinedione

4-Carbamoylphthalimide (2.00 g, 0.011 mol) was suspended in 12 ml ofN-methyl-2-pyrrolidinone, followed by the dropwise addition of 0.8 ml ofhydrazine hydrate. The obtained mixture was stirred at room temperaturefor 30 minutes, followed by the addition of 5.5 ml of 3N hydrochloricacid and 50 ml of water. The crystals thus precipitated were recoveredby filtration, washed with water and dried with hot air. The titlecompound (2.0 g) was obtained as a light brown crystal (yield: 94%).

1H-NMR (400 MHz, DMSO-d6) δ: 7.68(1H, br s), 8.12(1H, br d, J=8.4 Hz),8.32(1H, dd, J=8.4, 1.6 Hz), 8.39(1H, br s), 8.59(1H, br s), 11.69(2H,br s)

Preparative Example 6 6-Cyano-1,4-dichlorophthalazine

6-Carbamoyl-2,3-dihydro-1,4-phthalazinedione (1.00 g, 0.0049 mol) wassuspended in a mixture comprising 20 ml of phosphorus oxychloride and 20ml of thionyl chloride. The obtained suspension was heated under refluxone whole day and night and distilled in a vacuum to remove the solvent.The obtained residue was dissolved in methylene chloride, followed bywashing with water. The organic phase was dried over anhydrous magnesiumsulfate and purified by silica gel column chromatography to give 0.76 gof the title compound as a light brown crystal (yield: 70%).

Preparative Example 7 1,4,6-Trichlorophthalazine

The title compound was prepared from6-cyano-2,3-dihydro-1,4-phthalazinedione in a similar manner to that ofPreparative Example 3.

1H-NMR (400 MHz, CDCl3) δ: 8.01(1H, dd, J=9.0, 2.0 Hz), 8.29(1H, d,J=9.0 Hz), 8.31(1H, d, J=2.0 Hz)

Preparative Example 8 1,4-Dichloro-6-nitrophthalazine

The title compound was prepared from2,3-dihydro-6-nitro-1,4-phthalazinedione in a similar manner to that ofPreparative Example 3.

1H-NMR (400 MHz, CDCl3) δ: 8.02(1H, dd, J=9.0, 0.5 Hz), 8.83(1H, dd,J=9.0, 2.0 Hz), 9.20(1H, dd, J=2.0, 0.5 Hz)

Preparative Example 9 5-Chloro-3-(pyrid-3-yl)methylenephthalide

A mixture comprising 5.0 g of 4-chlorophthalic anhydride, 5.5 g of3-pyridylacetic acid hydrochloride and 0.5 g of anhydrous sodium acetatewas stirred without any solvent at 200° C. for 10 minutes.

Ethanol (100 ml) was added to the reaction mixture and the mixture thusobtained was cooled with ice to precipitate crystals, which wererecovered by filtration to give 2.68 g of the title compound as ayellowish-orange crystal.

1H-NMR (400 MHz, DMSO-d6) δ: 7.24(1H, s), 7.79(1H, dd, J=8.0, 2.0 Hz),7.89(1H, dd, J=8.0, 5.5 Hz), 8.03(1H, dd, J=8.0, 0.5 Hz), 8.35(1H, dd,J=2.0, 1.5 Hz), 8.56(1H, ddd, J=8.0, 2.0, 0.54 Hz), 8.74(1H, dd, J=5.5,1.5), 9.00(1H, d, J=2.0)

Preparative Example 10 6-Chloro-4-(3-pyridylmethyl)-1(2H)-phthalazinone

5-Chloro-3-(pyrid-3-yl)methylenephthalide (2.68 g) was dissolved in 100ml of ethanol, followed by the addition of 2.0 ml of hydrazinemonohydrate. The obtained mixture was heated under reflux for 4 hours,followed by the addition of 200 ml of water. The resulting mixture wasneutralized with dilute hydrochloric acid to precipitate crystals, whichwere recovered by filtration to give 1.87 g of the title compound as ayellow powder.

1H-NMR (400 MHz, DMSO-d6) δ: 4.37(2H, s), 7.33(1H, ddd, J=8.5, 4.5, 1.0Hz), 7.67-7.70(1H, m), 7.89(1H, dd, J=8.0, 2.0 Hz), 8.11(1H, d, J=2.0Hz), 8.26(1H, d, J=8.5 Hz), 8.44(1H, dd, J=4.5, 1.5), 8.58-8.59(1H, m),12.68(1H, s)

Preparative Example 11 1,6-Dichloro-4-(3-pyridylmethyl)phthalazine

6-Chloro-4-(3-pyridylmethyl)-1(2H)-phthalazinone (0.86 g) was suspendedin 10 ml of phosphorus oxychloride. The obtained suspension was heatedunder reflux for 2 hours and freed from the phosphorus oxychloride byvacuum distillation. The residue was dissolved in tetrahydrofuran. Theobtained solution was neutralized with triethylamine, followed by theaddition of water. The obtained mixture was extracted with ethylacetate. The organic phase was washed with water and a saturated aqueoussolution of common salt, dried over anhydrous magnesium sulfate andfreed from the solvent by vacuum distillation. The residue was purifiedby silica gel column chromatography to give 0.49 g of the title compoundas a pale yellow crystal.

1H-NMR (400 MHz, CDCl3) δ: 4.68(2H, s), 7.23(1H, dd, J=8.0, 4.5 Hz),7.63(1H, ddd, J=8.0, 2.0, 1.5 Hz), 7.90(1H, dd, J=8.5, 2.0 Hz), 8.03(1H,d, J=2.0 Hz), 8.28(1H, d, J=8.5 Hz), 8.50(1H, dd, J=4.5, 1.5 Hz),8.66(1H, d, J=2.0 Hz)

Preparative Example 12 4,6-Dichloro-1-(3-pyridylmethylphthalazine

A mixture comprising 5.0 g of 4-chlorophthalic anhydride, 5.5 g of3-pyridylacetic acid hydrochloride and 0.5 g of anhydrous sodium acetatewas stirred without any solvent at 200° C. for 10 minutes.

Ethanol (100 ml) was added to the reaction mixture and the resultingmixture was cooled with ice to precipitate crystals, which were filteredout and the filtrate was concentrated in a vacuum. The obtained residuewas subjected to silica gel column chromatography and the original-pointfraction was removed. The effluent was concentrated in a vacuum anddissolved in 50 ml of ethanol, followed by the addition of 2.0 g ofhydrazine monohydrate. The obtained mixture was heated under reflux for6 hours.

The solvent was distilled away in a vacuum and dilute aqueoushydrochloric acid was added to the residue to form a solution. Thissolution was neutralized with a saturated aqueous solution of sodiumhydrogencarboante and extracted with a chloroform/methanol mixture. Theorganic phase was dried over anhydrous magnesium sulfate and freed fromthe solvent by vacuum distillation. A mixture (2.27 g) comprising7-chloro-4-(3-pyridylmethyl)-1(2H)-phthalazinone and6-chloro-4-(3-pyridylmethyl)-1(2H)-phthalazinone was obtained as a lightbrown solid. This mixture (2.24 g, 8.25 mmol) was suspended in 20 ml ofphosphorus oxychloride. The obtained suspension was heated under refluxfor 2 hours and evaporated in a vacuum to dryness. The residue wasdissolved in dichloromethane. The obtained solution was neutralized witha saturated aqueous solution of sodium carbonate and extracted withdichloromethane twice. The organic phases were combined, washed withwater and a saturated aqueous solution of common salt, dried overmagnesium sulfate and freed from the solvent by vacuum distillation togive 1.22 g of a crude product. This crude product was purified bysilica gel column chromatography [dichloromethane/methanol (40:1)] togive 609 mg (2.10 mmol) of the title compound as a white crystal.

1H-NMR (400 MHz, CDCl3) δ: 4.71(2H, s), 7.20(1H, dd, J=8.0, 5.0 Hz),7.60(1H, ddd, J=8.0, 2.0, 1.5 Hz), 7.86(1H, dd, J=8.5, 2.0 Hz), 8.06(1H,d, J=8.5 Hz), 8.27(1H, d, J=2.0 Hz), 8.47(1H, dd, J=5.0, 1.5 Hz),8.65(1H, d, J=2.0 Hz)

Example 1 1-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine

6-Cyano-1,4-dichlorophthalazine (66.2 g) prepared in Preparative Example3 and 3-chloro-4-methoxybenzylamine (92 g) were suspended in 1200 ml oftetrahydrofuran, followed by the addition of 250 ml of triethylamine.The obtained mixture was heated under reflux for 6 hours.

The crystals thus precipitated were filtered out and the filtrate wasconcentrated in a vacuum. The residue was purified by silica gel columnchromatography [solvent: toluene/tetrahydrofuran (10:1)] to recover aless polar product. The title compound (59 g) was obtained as apale-yellow crystal.

M.p.: 213.0-214.5° C.

MASS: 359 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 3.87(3H, s), 4.78(2H, d, J=5.0 Hz), 5.75(1H,t, J=5.0 Hz), 6.87(1H, d, J=8.5 Hz), 7.31(1H, dd, J=8.5, 2.0 Hz),7.43(1H, d, J=2.0 Hz), 8.05(1H, dd, J=8.5, 1.5 Hz), 8.24(1H, dd, J=1.5,1.0 Hz), 8.29(1H, dd, J=8.5, 0.5 Hz)

Example 2 4-Chloro-1-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine

A more polar product prepared by repeating the same procedure as that ofExample 1 was recovered to give 27 g of the title compound as a whitecrystal.

M.p.: 122.0-123.5° C.

MASS: 359 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 3.91(3H, s), 4.80(2H, d, J=5.5 Hz), 5.43(1H,t, J=5.5 Hz), 6.92(1H, d, J=8.5 Hz), 7.33(1H, dd, J=8.5, 2.0 Hz),7.45(1H, d, J=2.0 Hz), 7.89(1H, dd, J=8.5, 0.5 Hz), 8.03(1H, dd, J=8.5,1.5 Hz), 8.55(1H, dd, J=1.5, 0.5 Hz)

Example 34-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxypiperidino)phthalazine

1-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine (10.0 g)prepared in Example 1 was dissolved in 50 ml ofN-methyl-2-pyrrolidinone, followed by the addition of 43.32 g of4-hydroxypiperidine- and 10 ml of diisopropylethylamine. The obtainedmixture was heated at 170° C. for 8 hours.

Ethyl acetate was added to the reaction mixture and the obtained mixturewas washed with water three times and with a saturated aqueous solutionof common salt once, dried over anhydrous magnesium sulfate and freedfrom the solvent by vacuum distillation. The residue was purified bysilica gel column chromatography [solvent: methylene chloride/methanol(30:1)] to give 10.1 g of the title compound as a yellow crystal.

M.p.: 172.0-173.5° C.

MASS: 424 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 1.70(1H, brs), 1.80-1.90(2H, m),2.07-2.15(2H, m), 3.05-3.15(2H, m), 3.50-3.60(2H, m), 3.87(3H, s),3.90-4.00(1H, m), 4.74(2H, d, J=5.0 Hz), 5.41(1H, t, J=5.0 Hz), 6.87(1H,d, J=8.5 Hz), 7.29(1H, dd, J=8.5, 2.0 Hz), 7.42(1H, d, J=2.0 Hz),7.95(1H, dd, J=8.5, 1.5 Hz), 8.12(1H, d, J=8.5 Hz), 8.21(1H, s)

Example 44-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxypiperidino)phthalazinehydrochloride

1-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine (10.0 g)prepared in Example 1 was dissolved in 50 ml of N-methyl-2-piperidone,followed by the addition of 43.32 g of 4-hydroxypyridine and 10 ml ofdiisopropylethylamine. The obtained mixture was heated at 170° C. for 8hours.

Ethyl acetate was added to the reaction mixture. The obtained mixturewas washed with water three times and with a saturated aqueous solutionof common salt once, dried over anhydrous magnesium sulfate and freedfrom the solvent by vacuum distillation. The residue was purified bysilica gel column chromatography [solvent: inethylene chloride/methanol(30:1)] to give 10.1 g of4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxypiperidino)phthalazineas a yellow crystal. This product (10.8 g) was suspended in a mixturecomprising 60 ml of ethanol and 30 ml of water, followed by the additionof 30 ml of 1N aqueous hydrochloric acid. The obtained mixture wasdissolved by heating and cooled by allowing to stand at roomtemperature.

The crystals thus precipitated were recovered by filtration and driedwith hot air at 80° C. overnight to give 9.37 g of the title compound asa yellow crystal.

M.p.: 217-227 (dec.) °C.

MASS: 424 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.61-1.70(2H, m), 1.90-1.97(2H, m),2.97-3.04(2H, m), 3.37-3.48(2H, m), 3.70-3.79(1H, m), 3.84(3H, s),4.70(2H, d, J=5.5 Hz), 7.15(1H, d, J=8.5 Hz), 7.44(1H, dd, J=8.5, 2.0Hz), 7.59(1H, d, J=2.0 Hz), 8.23(1H, d, J=8.5 Hz), 8.45(1H, d, J=8.5Hz), 9.33(1H, s), 10.10(1H, brs), 14.00(1H, brs)

Example 54-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-[4-oxo-1,4-dihydropyrid-1-yl)phthalazine

The title compound was prepared in a similar manner to that of Example3.

M.p.: 218-219° C.

MASS: 418 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 3.83(3H, s), 4.67(2H, d, J=5.6 Hz),7.11(1H, d, J=8.4 Hz), 7.27(2H, dd, J=1.6 Hz, 4.4 Hz), 7.36(1H, dd,J=8.4, 2.0 Hz), 7.48(1H, d, J=2.0 Hz), 8.18-8.24(2H, m), 8.31(1H, dd,J=8.4, 1.2 Hz), 8.56(2H, dd, J=1.6 Hz, 4.4 Hz), 9.02(1H, d, J=1.2 Hz)

Example 64-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-[4-(hydroxymethyl)piperidino]phthalazinehydrochloride

The title compound was prepared in a similar manner to that of Example4.

MASS: 438 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.40-1.50(2H, m), 1.61(1H, bs),1.78-1.84(2H, m), 2.82-2.91(2H, m), 3.33(2H, d, J=6.1 Hz), 3.52-3.62(2H,m), 3.83(3H, s), 4.71(2H, d, J=5.0 Hz), 7.14(1H, d, J=8.4 Hz), 7.45(1H,dd, J=8.4 Hz, 2.4 Hz), 7.61(1H, d, J=2.4 Hz), 8.21(1H, d, J=8.8 Hz),8.46(1H, d, J=8.8 Hz), 9.42(1H, s)

Example 74-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-(3-hydroxypropyl)aminophthalazine

The title compound was prepared in a similar manner to that of Example3.

M.p.: 132-135° C.

MASS: 398 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 1.91-1.98(2H, m), 3.40(1H, br s),3.71-3.76(1H, m), 3.80(2H, t, J=5.6 Hz), 3.81(2H, t, J=5.6 Hz), 3.91(3H,s), 4.68(2H, d, J=6.4 Hz), 5.30-5.34(1H, t, J=6.4 Hz), 6.92(1H, d, J=8.4Hz), 7.32(1H, dd, J=8.4, 2.4 Hz), 7.46(1H, d, J=2.4 Hz), 7.85(1H, d,J=8.8 Hz), 7.95(1H, dd, J=8.8, 1.6 Hz), 8.10(1H, d, J=1.6 Hz)

Example 8 4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-[4-(2-hydroxyethyl)piperidino]phthalazinehydrochloride

The title compound was prepared in a similar manner to that of Example 4

M.p.: 230 (dec.) °C.

MASS: 452 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.39-1.53(4H, m), 1.65(1H, m), 1.82(2H, m),2.87(2H, m), 3.50(2H, t, J=6.8 Hz), 3.56(2H, m), 3.85(3H, s), 4.74(2H,d, J=5.3 Hz), 7.15(1H, d, J=8.6 Hz), 7.49(1H, dd, J=8.6. 2.0 Hz),7.63(1H, d, J=2.0 Hz), 8.23(1H, d, J=8.6 Hz), 8.47(1H, dd, J=8.6, 1.5Hz), 9.53(1H, br s)

Example 94-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxy-4-methylpiperidino)phthalazinehydrochloride

The title compound was prepared in a similar manner to that of Example4.

M.p.: 230-240° C. (dec.)

MASS: 438 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.22(3H, s), 1.61-1.71(2H, m),1.73-1.84(2H, m), 3.18-3.33(4H, m), 3.85(3H, s), 4.76(2H, d, J=5.1 Hz),7.15(1H, d, J=8.6 Hz), 7.51(1H, dd, J=8.6, 2.0 Hz), 7.66(1H, d, J=2.0Hz), 8.23(1H, d, J=8.4 Hz), 8.46(1H, dd, J=8.4, 1.0 Hz). 9.63(1H, s)

Example 104-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-(3-hydroxypiperidino)phthalazinehydrochloride

The title compound was prepared in a similar manner to that of Example4.

M.p.: 189-199° C.

MASS: 424 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.45(1H, m), 1.71(1H, m), 1.84-1.97(2H, m),2.86(1H, m), 2.98(1H, m), 3.32(1H, m), 3.42(1H, m), 3.83(1H, m),3.85(3H, s), 4.76(2H, d, J=5.7 Hz), 7.16(1H, d, J=8.6 Hz), 7.51(1H, dd,J=8.6, 2.0 Hz), 7.66(1H, d, J=2.0 Hz), 8.31(1H, d, J=8.4 Hz), 8.49(1H,dd, J=8.4, 1.3 Hz), 9.61(1H, s)

Example 114-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-(2-pyridylmethyl)aminophthalazinedihydrochloride

The title compound was prepared in a similar manner to that of Example4.

M.p.: 188-190° C.

MASS: 431 (MH+)

1H-NMR (400 MHz, CD30D) δ: 3.83(3H, s), 4.62(2H, s), 5.05(2H, s),7.08(1H, d, J=8.5 Hz), 7.35(1H, dd, J=8.5, 2.0 Hz), 7.47(1H, d, J=2.0Hz), 7.98(1H, ddd, J=8.0, 6.0, 1.5 Hz), 8.16(1H, d, J=8.0 Hz), 8.48(1H,dd, J=8.5, 1.5 Hz), 8.57(1H, ddd, J=8.0, 8.0, 1.5 Hz), 8.62(1H, d, J=8.5Hz), 8.76-8.78(1H, m), 9.06(1H, d, J=1.5 Hz)

Example 124-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-(4-pyridylmethyl)aminophthalazinedihydrochloride

The title compound was prepared in a similar manner to that of Example4.

M.p.: 212-214° C.

MASS: 431 (MH+)

1H-NMR (400 MHz, CD30D) δ: 3.88(3H, s), 4.61(2H, s), 4.97(2H, s),7.08(1H, d, J=8.5 Hz), 7.34(1H, dd, J=8.5, 2.0 Hz), 7.47(1H, d, J=2.0Hz), 8.11-8.14(2H, m), 8.48(1H, dd, J=8.5, 1.5 Hz), 8.61(1H, d, J=8.5Hz), 8.77-8.79(2H, m), 9.04(1H, d, J=1.5 Hz)

Example 134-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-(3-pyridylmethyl)aminophthalazinedihydrochloride

The title compound was prepared in a similar manner to that of Example4.

M.p.: 195.0-196.5° C.

MASS: 431 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 3.84(3H, s), 4.59-4.63(2H, m),4.78-4.82(2H, m), 7.12(1H, d, J=8.5 Hz), 7.40(1H, dd, J=8.5, 2.0 Hz),7.55(1H, d, J=2.0 Hz), 7.92(1H, dd, J=8.0, 5.5 Hz), 8.46-8.52(1H, m),8.58(1H, dd, J=8.5, 1.5 Hz), 8.77(1H, d, J=5.5 Hz), 8.82-8.92(1H, m),8.93(1H, d, J=1.5 Hz), 9.36-9.42(1H, m)

Example 144-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-[N-(3-hydroxypropyl)-N-methylamino]phthalazine

The title compound was prepared in a similar manner as that of Example3.

M.p: amorphous

MASS: 412 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.72-1.79(1H, m), 2.83(3H, s) 3.14-3.22(2H,m), 3.41-3.48(2H, m), 3.83(3H, s), 4.45(1H, t, J=4.8 Hz), 4.64(2H, d,J=5.6 Hz), 7.10(1H, d, J=8.0 Hz), 7.36(1H, dd, J=8, 2 Hz), 7.46(1H, d,J=2 Hz), 7.85(1H, t, J=5.6 Hz), 8.13-8.22(2H, m), 8.88(1H, d, J=1.2 Hz)

Example 154-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-[4-(2-pyridyl)piperazin-1-yl]phthalazinedihydrochloride

The title compound was prepared in a similar manner to that of Example4.

M.p.: 205-215 (dec.) °C.

MASS: 486 (MH+)

1H-NMR (400 MHz, CD30D) δ: 3.59(4H, m), 3.90(3H, s). 4.01(4H, m),4.74(2H, s), 4.07(1H, m), 7.12(1H, d, J=8.6 Hz), 7.41(1H, dd, J=8.6, 2.4Hz), 7.50(1H, d, J=9.2 Hz), 7.54(1H, d, J=2.4 Hz), 8.02(1H, m), 8.11(1H,m), 8.44(1H, dd, J=8.4, 1.6 Hz), 8.49(1H, dd, J=8.4, 0.8 Hz), 9.09(1H,dd, J=1.6, 0.8 Hz)

Example 164-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-[4-(2-pyrimidyl)piperazin-1-yl]phthalazinedihydrochloride

The title compound was prepared in a similar manner to that of Example4.

M.p.: 205-209 (dec.) °C.

MASS: 487 (MH+)

1H-NMR (400 MHz, CD30D) δ: 3.52(4H, m), 3.90(3H, s), 4.17(4H, m),4.73(2H, s), 6.94(1H, t, J=4.8 Hz), 7.12(1H, d, J=8.4 Hz), 7.41(1H, dd,J=8.4, 2.4 Hz), 7.54(1H, d, J=2.4 Hz), 8.43(1H, dd, J=8.4, 1.6 Hz),8.49(1H, dd, J=8.4, 0.6 Hz), 8.57(2H, d, J=4.8 Hz), 9.08(1H, dd, J=1.6,0.6 Hz)

Example 171-(4-Carbamoylpiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine

The title compound was prepared in a similar manner to that of Example3.

M.p.: 228-230 (dec.)

MASS: 451 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.80-1.95(4H, m), 2.30(1H, m), 2.82(2H, m),3.44(2H, m), 3.82(3H, s), 4.64(2H, d, J=5.8 Hz), 6.80(1H, br s),7.10(1H, d, J=8.4 Hz), 7.32(1H, br s), 7.35(1H, dd, J=8.4, 2.0 Hz),7.46(1H, d, J=2.0 Hz), 7.91(1H, t, J=5.8 Hz), 8.08(1H, d, J=8.8 Hz),8.20(1H, dd, J=8.8, 1.2 Hz), 8.89(1H, d, J=1.2 Hz)

Example 184-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-[4-(2-hydroxyethyl)piperazin-1-yl]phthalazinedihydrochloride

4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-[4-(2-hydroxyethyl)piperazin-1-yl]phthalazine(12.0 g, 26.5 mmol) prepared in a similar manner to that of Example 3was suspended in 600 ml of acetone, followed by the addition of 60 ml of1N hydrochloric acid. The obtained mixture was stirred at roomtemperature for 30 minutes to precipitate crystals, which were recoveredby filtration and dried at 90° C. for 6 hours to give 13.06 g of thetitle compound as a pale-yellow powder.

M.p.: 185-189° C.

MASS: 453 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 3.25-3.31(2H, m), 3.37-3.52(5H, m),3.60-3.70(4H, m), 3.85(3H, s), 3.86(2H, br t, J=5.7 Hz), 4.82(2H, d,J=5.7 Hz), 7.16(1H, d, J=8.8 Hz), 7.53(1H, dd, J=8.8, 2.0 Hz), 7.67(1H,d, J=2.0 Hz), 8.33(1H, d, J=8.4 Hz), 8.65(1H, dd, J=8.4, 1.1 Hz),9.67(1H, s), 11.14(br, 1H)

Example 194-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-(4-oxopiperidino)phthalazinehydrochloride

4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-(4,4-ethylenedioxypiperidino)phthalazine(565 mg, 1.21 mmol) prepared in a similar manner to that of Example 3was dissolved in 5 ml of trifluoroacetic acid. The obtained solution wasstirred at room temperature for 18 hours and evaporated in a vacuum todryness. The residue was dissolved in dichloromethane. The obtainedsolution was neutralized with a saturated aqueous solution of sodiumhydrogencarbonate and extracted with dichloromethane twice. The organicphases were combined, washed with water and a saturated aqueous solutionof common salt, dried over magnesium sulfate and freed from the solventby vacuum distillation. The crude product thus obtained was purified bysilica gel column chromatography [ethyl acetate/hexane (3:1)] to give565 mg of a pale-yellow solid. This solid was recrystallized from 50%aqueous ethanol to give 423 mg (1.00 mmol) of4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-oxo-piperidino)phthalazine.This compound was convereted into a hydrochloride in the same manner asthat employed in Example 4 for the formation of hydrochloride.

M.p.: 206° C. (dec.)

MASS: 422 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 2.62-2.68(4H, m), 3.55-3.61(4H, m),3.85(3H, s), 4.77(2H, d, J=5.5 Hz), 7.15(1H, d, J=8.5 Hz), 7.49(1H, dd,J=8.5, 2.0 Hz), 7.64(1H, d, J=2.0 Hz), 8.40(1H, d, J=8.5 Hz), 8.50(1H,dd, J=8.5, 1.5 Hz), 9.55(1H, d, J=1.5 Hz)

Example 201-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)-amino-6-cyanophthalazinehydrochloride

1-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine (2 g)prepared in Example 1 and t-butyl isonipecotate (2 g) were dissolved in20 ml of N-methyl-2-pyrrolidone. The obtained solution was heated at170° C. for 5 hours and cooled, followed by the addition of water. Theobtained mixture was extracted with ethyl acetate. The organic phase waswashed with water, dried over anhydrous magnesium sulfate andconcentrated in a vacuum. The obtained residue was subjected to silicagel column chromatography and eluted with toluene/tetrahydrofuran (10:1)to give 1.6 g of1-(4-tert-butoxycarbonyl-piperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine.

1-(4-tert-Butoxycarbonylpiperidino-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine(1.2 g) was stirred in 20 ml of formic acid at room temperature for 20hours. The resulting mixture was concentrated in a vacuum and theobtained residue was subjected to silica gel column chromatography andeluted with dichloromethane/methanol (10:1) to give 1.05 g of the titlecompound.

M.p.: >270° C.

MASS: 452 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.88-1.93(2H, m), 1.96-2.03(2H, m),2.50-2.59(1H, m), 2.92-3.01(2H, m), 3.50-3.58(2H, m), 3.85(3H, s),4.74(2H, d, J=5.2 Hz), 7.16(1H, d, J=8.4 Hz), 7.48(1H, dd, J=8.4, 2.4Hz), 7.63(11H, d, J=2.4 Hz), 8.26(1H, d, J=8.4 Hz), 8.46(1H, dd, J=8.4,1.2 Hz), 9.49(1H, d, J=1.2 Hz)

Example 21 4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1(2H)-phthalazinone

1-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine (1.0 g)prepared in Example 1 was dissolved in 10 ml of N-methyl-2-piperidone,followed by the addition of 0.26 ml of acetic acid and 2.1 ml ofdiisopropylethylamine. The obtained mixture was stirred at 170° C. for 7hours, followed by the addition of 100 ml of water. The crystals thusprecipitated were recovered by filtration.

The crystals were recrystallized from ethanol/water to give 0.6 g of thetitle compound as a yellow crystal.

M.p.: 292.5-294° C.

MASS: 341 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 3.81(3H, s), 4.36(2H, d, J=5.5 Hz),7.07(1H, d, J=8.5 Hz), 7.29(1H, dd.

J=8.5, 2.0 Hz), 7.30(1H, t, J=5.5 Hz), 7.41(1H, d, J=2.0 Hz), 8.19(1H,dd, J=8.0, 1.0 Hz), 8.32(1H, d, J=8.0 Hz), 8.73(1H, d, J=1.0 Hz),11.86(1H, s)

Example 222-tert-Butoxycarbonylmethyl-4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1(2H)-phthalazinone

4-(3-Chloro-4-methoxybenzyl)amino-6-cyanol-1(2H)-phthalazinone (0.20 g)prepared in Example 21 was dissolved in 5 ml ofN-methyl-2-pyrrolidinone, followed by the addition of 0.14 g of t-butylbromoacetate and 0.24 g of potassium carbonate. The obtained mixture wasstirred at 80° C. for 4 hours and poured into water, followed byextraction with ethyl acetate. The organic phase was washed with watertwice and with a saturated aqueous solution of common salt, dried overanhydrous magnesium sulfate and freed from the solvent by vacuumdistillation. The title compound (0.41 g) was obtained as a yellowcrystal.

M.p.: 173.5-175° C.

MASS: 454 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.49(9H, s), 3.90(3H, s), 4.37(2H, d, J=5.0Hz), 4.91(2H, d, J=5.0 Hz), 6.90(1H, d, J=8.5 Hz), 7.25(1H, dd, J=8.5,2.0 Hz), 7.42(1H, d, J=2.0 Hz), 7.93(1H, dd, J=8.0, 1.5 Hz), 8.00(1H, d,J=1.5 Hz), 8.53(1H, d, J=8.0 Hz)

Example 232-Carboxymethyl-4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1(2H)-phthalazinone

Trifluoroacetic acid (5 ml) was added to 0.41 g of the t-butyl esterprepared in Example 22. The obtained mixture was stirred at roomtemperature for one hour and freed from the trifluoroacetic acid byvacuum distillation. The obtained residue was recrystallized fromethanol/water to give 0.06 g of the title compound as a yellow crystal.

M.p.: 173-175° C.

MASS: 399 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 3.81(3H, s), 4.34(2H, d, J=5.5 Hz),4.62(2H, s), 7.06(1H, d, J=8.5 Hz), 7.32(1H, dd, J=8.5, 2.0 Hz),7.43(1H, t, J=5.5 Hz), 7.45(1H, d, J=2.0 Hz), 8.22(1H, dd, J=8.0 Hz, 1.0Hz), 8.34(1H, d, J=8.0 Hz), 8.74(1H, d, J=1.0 Hz), 12.95(1H, br s)

Example 244-(3-Chloro-4-methoxybenzyl)amino-6-cyano-2-[3-(tetrahydropyran-2-yloxy)propyl]-1(2H)-phthalazinone

4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1(2H)-phthalazinone (0.20 g)prepared in Example 21 was dissolved in 5 ml ofN-methyl-2-pyrrolidinone, followed by the addition of 0.24 g of3-bromopropyl 2-tetrahydropyranyl ether and 0.24 g of potassiumcarbonate. The obtained mixture was stirred at 50° C. for 4 hours andpoured into water, followed by extraction with ethyl acetate. Theorganic phase was washed with water twice and with a saturated aqueoussolution of common salt, dried over anhydrous magnesium sulfate andfreed from the solvent by vacuum distillation. The residue was purifiedby silica gel column chromatography [solvent: n-hexane/ethyl acetate(1:1)] to give 0.20 g of the title compound as a yellow crystal.

1H-NMR (400 MHz, CDCl3) δ: 1.44-1.83(6H, m), 2.08-2.17(2H, m),3.45-3.51(2H, m), 3.81-3.87(2H, m), 3.89(3H, s), 4.17-4.30(2H, m),4.46(2H, d, J=5.5 Hz), 4.57-4.59(1H, m), 5.02(1H, t, J=5.5 Hz), 6.90(1H,d, J=8.5 Hz), 7.28(1H, dd, J=8.5, 2.0 Hz), 7.44(1H, d, J=2.0 Hz),7.93(1H, dd, J=8.0, 1.5 Hz), 8.06(1H, dd, J=1.5, 1.0 Hz), 8.55(1H, dd,J=8.0, 0.5 Hz)

Example 254-(3-Chloro-4-methoxybenzyl)amino-6-cyano-2-(3-hydroxypropyl)-1(2H)-phthalazinone

Methanol (20 ml) and 1N hydrochloric acid (2 ml) were added to the4-(3-chloro-4-methoxybenzyl)amino-6-cyano-2-[3-(tetrahydropyran-2-yloxy)propyl]-1(2H)-phthalazinone(0.20 g) prepared in Example 24. The obtained mixture was stirred atroom temperature for 3 hours.

The solvent was distilled away in a vacuum and the residue wasrecrystallized from ethanol/water to give 0.14 g of the title compoundas a yellow crystal.

M.p.: 191.5-193.0° C.

MASS: 399 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.79(2H, quint, J=6.0 Hz), 3.40(2H, q,J=6.0 Hz), 3.81(3H, s), 3.99(2H, t, J=6.0 Hz), 4.36(2H1, d, J=5.5 Hz),7.07(1H, d, J=8.5 Hz), 7.33(1H, dd, J=8.5, 2.0 Hz), 7.45(1H, t, J=5.0Hz), 7.46(1H, d, J=2.0 Hz), 8.19(1H, dd, J=8.0, 1.5 Hz), 8.34(1H, d,J=8.0 Hz), 8.71(1H, d, J=1.5 Hz)

Example 266-Cyano-1-(4-hydroxypiperidino)-4-(3,4-methylenedioxy-benzyl)aminophthalazinehydrochloride

The title compound was prepared from1-chloro-6-cyano-4-(3,4-methylenedioxybenzyl)aminophthalazine preparedin a similar manner to that of Example 1 in a similar manner to that ofExample 4.

MASS: 404 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.52-1.70(2H, m), 1.86-1.95(2H, m),2.94-3.02(2H, m), 3.38-3.46(2H, m), 3.69-3.75(1H, m), 4.73(2H, d, J=5.0Hz), 6.87(1H, d, J=8.0 Hz), 7.04(1H, dd, J=8, 1.6 Hz), 7.16(1H, d, J=1.6Hz), 8.19(1H, d, J=8.4 Hz), 8.44(1H, d, J=8.4 Hz), 9.69(1H, s)

Example 27 4-(3-Chloro-4-methoxybenzyl)amino-1,6-dichlorophthalazine

The title compound was prepared from 1,4,6-trichlorophthalazine preparedin Preparative Example 7 in a similar manner to that of Example 1.

M.p.: 197-198.5° C.

MASS: 368 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 3.89(3H, s), 4.78(2H, d, J=5.5 Hz), 5.32(1H,t, J=5.5 Hz), 6.89(1H, d, J=8.5 Hz), 7.32(1H, dd, J=8.5, 2.0 Hz),7.45(1H, d, J=2.0 Hz), 7.77(1H, d, J=2.0 Hz), 7.82(1H, dd, J=9.0, 2.0Hz), 8.15(1H, d, J=9.0 Hz)

Example 28 1-(3-Chloro-4-methoxybenzyl)amino-4,6-dichlorophthalazine

The title compound was prepared from 1,4,6-trichlorophthalazine preparedin Preparative Example 7 in a similar manner to that of Example 2.

M.p.: 168-169.5° C.

MASS:. 368 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 3.90(3H, s), 4.78(2H, d, J=5.5 Hz), 5.30(1H,t, J=5.5 Hz), 6.91(1H, d, J=8.5 Hz), 7.33(1H, dd, J=8.5, 2.0 Hz),7.45(1H, d, J=2.0 Hz), 7.72(1H, d, J=9.0 Hz), 7.78(1H, dd, J=9.0, 2.0Hz), 8.18(1H, d, J=2.0 Hz)

Example 296-Chloro-4-(3-chloro-4-methoxybenzyl)amino-1-(3-hydroxypyrrolidino)phthalazine

In a similar manner to that of Example 3, the title compound wasprepared from 4-(3-chloro-4-methoxybenzyl)amino-1.6-dichlorophthalazineprepared in Example 27.

M.p.: 191-193° C.

MASS: 419 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 2.01-2.08(1H, m), 2.14-2.24(1H, m),3.56-3.64(1H, m), 3.73(1H, dt, J=14 Hz, 4 Hz), 3.82(1H, dd, J=6 Hz, 16Hz), 3.88(3H, s), 3.94(1H, dt, J=14 Hz, 16 Hz), 4.58-4.62(1H, m),4.69(2H, d, J=6 Hz), 4.83-4.90(1H, br t), 6.89(1H, d, J=8.4 Hz),7.31(1H, dd, J=2.2 Hz, 8.4 Hz), 7.45(1H, d, J=2.2 Hz), 7.68(1H, dd,J=2.0 Hz, 8.8 Hz), 7.72(1H, d, J=2.0 Hz), 8.10(1H, d, J=8.8 Hz)

Example 30(R)-6-Chloro-4-(3-chloro-4-methoxybenzyl)amino-1-[2-(hydroxymethyl)pyrrolidino]phthalazinehydrochloride

In a similar manner to that of Example 4, the title compound wasprepared from 4-(3-chloro-4-methoxybenzyl)amino-1,6-dichlorophthalazineprepared in Example 27.

M.p.: 163-165° C.

MASS: 433 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 1.80-1.95(1H, m), 1.95-2.04(1H, m),2.15-2.24(1H, m), 3.42-3.48(1H, m), 3.75(1H, dd, J=16 Hz, 8 Hz),3.86(1H, dd, J=6 Hz, 16 Hz), 3.90(3H, s), 3.90-3.97(1H, m), 4.70(2H, d,J=6 Hz), 4.70-4.77(1H, m), 4.83(1H, br, t, J=6 Hz), 6.91(1H, d, J=8.4Hz), 7.31(1H, dd, J=8.4, 2.2 Hz), 7.45(1H, d, J=2.2 Hz), 7.69(1H, dd,J=8.4 Hz, 2.0 Hz), 7.72(1H, d, J=2.0 Hz), 8.08(1H, d, J=2.0 Hz)

Example 316-Chloro-4-(3-chloro-4-methoxybenzyl)amino-1-(imidazol-1-yl)phthalazine

In a similar manner to that of Example 3, the title compound wasprepared from 4-(3-chloro-4-methoxybenzyl)amino-1,6-dichlorophthalazineprepared in Example 27.

M.p.: 221-222.5° C.

1H-NMR (400 MHz, CDCl3) δ: 3.91(3H, s), 4.86(2H, d, J=5.5 Hz), 5.56(1H,t, J=5.5 Hz), 6.93(1H, d, J=8.5 Hz), 7.31(1H, br s), 7.36(1H, dd, J=8.5,2.0 Hz), 7.41-7.42(1H, m), 7.48(1H, d, J=2.0 Hz), 7.67(1H, d, J=9.0 Hz),7.81(1H, dd, J=9.0, 2.0 Hz), 7.99(1H, br s)

Example 326-Chloro-4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxypiperidino)phthalazinehydrochloride

In a similar manner to that of Example 4, the title compound wasprepared from 4-(3-chloro-4-methoxybenzyl)amino-1.6-dichlorophthalazineprepared in Example 27.

M.p.: 229-232 (dec.) ° C.

MASS: 433 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.60-1.70(2H, m), 1.86-1.96(2H, m),2.95-3.06(2H, m), 3.38-3.48(2H, m), 3.69-3.78(1H, m). 3.92(3H, s),4.68(2H, d, J=4.6 Hz), 7.13(1H, d. J=8.8 Hz), 7.43(1H, d, J=8.8 Hz),7.58(1H, s), 8.06-8.15(2H, m), 9.01(1H, s)

Example 331.6-Bis-(4-hydroxypiperidino)-4-(3-chloro-4-methoxybenzyl)aminophthalazine

The title compound was prepared in a similar manner to that of Example32 as a more polar product.

MASS: 498 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.40-1.51(2H, m), 1.55-1.65(2H, m),1.80-1.91(4H, m), 2.78-2.85(2H, m), 3.03-3.11(2H, m), 3.27-3.34(2H, m),3.56-3.66(1H, m), 3.66-3.25(1H, m), 3.76-3.82(2H, m), 3.80(3H, s),4.60(2H, d, J=5.3 Hz). 4.68(1H. d, J=4.1 Hz), 4.22(1H, d, J=4.1 Hz),7.34(1H, d, J=8.6 Hz), 7.28(1H, dd, J=8.6 Hz, 2.0 Hz),

Example 346-Chloro-4-(3-chloro-4-methoxybenzyl)amino-1-morpholinophthalazinehydrochloride

In a similar manner to that of Example 4, the title compound wasprepared from 4-(3-chloro-4-methoxybenzyl)amino-1,6-dichlorophthalazineprepared in Example 27.

M.p.: 255-261 (dec.) ° C.

MASS: 419 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 3.20-3.23(4H, m), 3.82-3.96(4H, m),3.85(3H, s), 4.74(2H, d, J=6.0 Hz), 7.15(1H, d, J=8.8 Hz), 7.48(1H, dd,J=8.8, 2.0 Hz), 7.63(1H, d, J=2.0 Hz), 8.13(1H, dd, J=8.8, 2.0 Hz),8.21(1H, d, J=8.8 Hz), 9.16(1H, d, J=2.0 Hz), 10.50(1H, br t), 13.97(1H,br s)

Example 356-Chloro-4-(3-chloro-4-methoxybenzyl)amino-1-(3-hydroxypropyl)aminophthalazine

In a similar manner to that of Example 3, the title compound wasprepared from 4-(3-chloro-4-methoxybenzyl)amino-1,6-dichlorophthalazineprepared in Example 27.

M.p.: 131-138° C.

MASS: 407 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 1.83-1.94(2H, m), 3.75(2H, t, J=5.4 Hz),3.80(2H, t, J=5.4 Hz), 3.90(3H, s), 4.59(1H, br t, J=4.8 Hz), 4.66(2H,d, J=4.8 Hz), 5.14(1H, br t), 6.91(1H, d, J=8.4 Hz), 7.32(1H, dd, J=8.4,2.4 Hz), 7.45(1H, d, J=2.4 Hz), 7.69(2H, s), 7.72(1H, d, J=1.6 Hz)

Example 366-Chloro-4-(3-chloro-4-methoxybenzyl)amino-1-[4-(hydroxymethyl)piperidino]phthalazine

In a similar manner to that of Example 3, the title compound wasprepared from 4-(3-chloro-4-methoxybenzyl)amino-1,6-dichlorophthalazineprepared in Example 27.

M.p.: 128-131° C.

MASS: 447 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 1.48-1.63(3H, m), 1.76(1H, m), 1.92(2H, m),3.01(2H, dt, J=12.3, 2.0 Hz), 3.59-3.67(4H, m), 3.89(3H, s), 4.74(2H, d,J=5.1 Hz), 4.99(1H, br t, J=5.1 Hz), 6.89(1H, d, J=8.4 Hz), 7.32(1H, dd,J=8.4, 2.2 Hz), 7.45(1H, d, J=2.2 Hz), 7.70(11H, dd, J=8.6, 1.8 Hz),7.73(1H, d, J=1.8 Hz), 7.99(1H, d, J=8.6 Hz)

Example 376-Chloro-4-(3-chloro-4-methoxybenzyl)amino-1-[4-(2-hydroxyethyl)piperidino]phthalazine

In a similar manner to that of Example 3, the title compound wasprepared from 4-(3-chloro-4-methoxybenzyl)amino-1,6-dichlorophthalazineprepared in Example 27.

M.p.: 153-155° C.

MASS: 461 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 1.41(br s), 1.54(2H, m), 1.60-1.76(3H, m),1.88(2H, m), 2.98(2H, dt, J=12.5, 1.8 Hz), 3.59(2H, m), 3.78(2H, br t,J=6.2 Hz), 3.89(3H, s), 4.74(2H, d, J=5.3 Hz), 5.00(1H, br t, J=5.3 Hz),6.89(1H, d, J=8.4 Hz), 7.31(1H, dd, J=8.4, 2.2 Hz), 7.45(1H, d, J=2.2Hz), 7.69(1H, dd, J=8.8, 2.0 Hz), 7.73(1H, d, J=2.2 Hz), 7.98(1H, d,J=8.8 Hz)

Example 386-Chloro-4-(3-chloro-4-methoxybenzyl)amino-1-ethoxyphthalazine

A solution of 120 mg of 60% oily sodium hydride in 20 ml of ethanol wasadded to 1.0 g of4-(3-chloro-4-methoxybenzyl)amino-1,6-dichlorophthalazine prepared inExample 27. The obtained mixture was heated at 150° C. in a sealed tubeovernight, cooled and concentrated in a vacuum. The residue wasdissolved in ethyl acetate. The obtained solution was washed with waterand a saturated aqueous solution of common salt, dried over anhydrousmagnesium sulfate and concentrated in a vacuum. The obtained residue wassubjected to silica gel column chromatography and eluted withdichloromethane/methanol (50:1) to give 0.9 g of the title compound.

M.p.: 111-115° C.

MASS: 387 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.46(3H, t, J=7.2 Hz), 3.82(3H, s),4.43(2H, q, J=7.2 Hz), 4.59(2H, d, J=5.6 Hz), 7.08(1H, d, J=8.4 Hz),7.33(1H, dd, J=8.4, 2.0 Hz), 7.44(1H, d, J=2.0 Hz), 7.65(1H, t, J=5.6Hz), 7.90(1H, dd, J=8.8, 2.0 Hz), 8.03(1H, d, J=8.8 Hz), 8.45(1H, d,J=2.0 Hz)

Example 396-Chloro-4-(3-chloro-4-methoxybenzyl)amino-1-(3-hydroxypropyloxy)phthalazine

60% Sodium hydride (0.12 g, 3.0 mmol) was added to 8 ml of1,3-propanediol. The obtained mixture was stirred at room temperaturefor one hour, followed by the addition of 1.0 g (2.7 mmol) of thecompound prepared in Example 27. The obtained mixture was stirred at150° C. for one hour, followed by the addition of water. The resultingmixture was extracted with ethyl acetate. The organic phase was washedwith water and a saturated aqueous solution of common salt, dried overanhydrous magnesium sulfate and freed from the solvent by distillation.The residue was purified by silica gel column chromatography [solvent:dichloromethane/methanol (30:1)] and recrystallized from aqueous ethanolto give 0.58 g of the title compound as white needles.

M.p.: 124-126° C.

MASS: 408 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 2.11(2H, quintet, J=8.0 Hz), 3.22(1H, br s),3.82(2H, br), 3.87(3H, s), 4.67(2H, d, J=5.3 Hz), 4.70(2H, t, J=6.0 Hz),5.08(1H, t, J=5.3 Hz), 6.85(1H, d, J=8.4 Hz), 7.28(1H, dd, J=8.4, 2.2Hz), 7.42(1H, d, J=2.2 Hz), 7.69(1H, dd, J=8.8, 1.8 Hz), 7.75(1H, d,J=1.8 Hz), 8.05(1H, d, J=8.8 Hz)

Example 406-Chloro-4-(3-chloro-4-methoxybenzyl)amino-1-[N-(3-hydroxypropyl)-N-methylamino]phthalazine

The compound (1.0 g, 2.7 mmol) prepared in Example 27 was dissolved in 9ml of N-methyl-2-pyrrolidone, followed by the addition of 0.7 g (4.1mmol) of N-methylpropanolamine hydrobromide and 1.14 g (8.2 mmol) ofanhydrous potassium carbonate. The obtained mixture was stirred at 170°C. for 7.5 hours, followed by the addition of water. The resultingmixture was extracted with ethyl acetate. The organic phase was washedwith water and a saturated aqueous solution of common salt, dried overanhydrous magnesium sulfate and freed from the solvent by distillation.The residue was purified by silica gel column chromatography [solvent:dichloromethane/methanol (20:1)] and crystallized fromdichloromethane/ether to give 37 mg of the title compound as whiteneedles.

M.p.: 115-117° C.

MASS: 421 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 1.95(2H, quintet, J=6.0 Hz), 2.85(1H, br s),2.99(3H, s), 3.51(2H, t, J=6.0 Hz), 3.75(2H, t, J=6.0 Hz), 3.90(3H, s),4.74(2H, d, J=5.3 Hz), 4.95(1H, br), 6.91(1H, d, J=8.4 Hz), 7.33(1H, dd,J=8.4, 2.0 Hz), 7.46(1H, d, J=2.2 Hz), 7.72(1H, dd, J=9.3, 2.0 Hz),7.72(1H, d, J=2.0 Hz), 8.05(1H, d, J=9.3 Hz)

Example 416-Chloro-4-(3-chloro-4-methoxybenzyl)amino-1-(4-oxopiperidino)phthalazinehydrochloride

In a similar manner to that of Example 19, the title compound wasprepared from the compound prepared in Example 27.

M.p.: 197 (dec.) ° C.

MASS: 431 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 2.62-2.66(4H, m), 3.57-3.61(4H, m),3.85(3H, s), 4.73(2H, d, J=6.0 Hz), 7.16(1H, d, J=8.5 Hz), 7.45(1H, dd,J=8.5, 2.0 Hz), 7.60(1H, d, J=2.0 Hz), 8.17(1H, dd, J=9.0, 2.0 Hz),8.28(1H, d, J=9.0 Hz), 9.02(1H, br s)

Example 426-Chloro-4-(3-chloro-4-methoxybenzyl)amino-1-(4-ethoxycarbonylpiperidino)phthalazine

In a similar manner to that of Example 3, the title compound wasprepared from the compound prepared in Example 27.

M.p.: 162-164.5° C.

MASS: 489 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 1.29(3H, t, J=7.0 Hz), 1.96-2.14(4H, m),2.50-2.58(1H, m), 2.99-3.07(2H, m), 3.57-3.63(2H, m), 3.91(3H, s),4.19(2H, q, J=7.0 Hz), 4.75(2H, d, J=5.0 Hz), 4.92(1H, t, J=5.0 Hz),6.91(1H, d, J=8.5 Hz), 7.32(1H, dd, J=8.5, 2.0 Hz), 7.46(1H, d, J=2.0Hz), 7.70(1H, d, J=2.0 Hz), 7.71(1H, dd, J=8.0, 2.0 Hz), 7.99(1H, d,J=8.0 Hz)

Example 43

1-(4-Carboxypiperidino)-6-chloro-4-(3-chloro-4-methoxybenzyl)aminophthalazine

Methanol (50 ml), tetrahydrofuran (50 ml) and 1N aqueous solution (10ml) of sodium hydroxide were added to 3.00 g of the compound prepared inExample 42. The obtained mixture was stirred at room temperatureovernight and freed from the solvent by vacuum distillation. The residuewas dissolved in 100 ml of water, followed by the addition of 10 ml of1N hydrochloric acid. The crystals thus precipitated were recovered byfiltration to give 2.76 g of the title compound as a pale-yellowcrystal.

M.p.: 239.5-242° C. (dec.)

MASS: 489 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.78-1.90(2H. m), 1.93-2.00(21, m),2.40-2.50(1H, m), 2.83-2.90(2H, m), 3.35-3.45(2H, m), 3.82(3H, s),4.61(2H, d, J=5.5 Hz), 7.09(1H, d, J=8.5 Hz), 7.33(1H, dd, J=8.5, 2.0Hz), 7.43(1H, d, J=2.0 Hz), 7.75(1H, t, J=5.5 Hz), 7.88(1H, dd, J=9.0,2.0 Hz), 7.98(1H, d, J=9.0 Hz), 8.44(1H, d, J=2.0 Hz)

Example 441-[N3-Carboxypropyl)-N-methylamino]-6-chloro-4-(3-chloro-4-methoxybenzyl)aminophthalazine

6-Chloro-1-[N-(3-ethoxycarbonylpropyl)-N-methylamino]-4-(3-chloro-4-methoxybenzyl)aminophthalazinewas prepared from the compound prepared in Example 27 in a similarmanner to that of Example 3 and further converted into the titlecompound in a similar manner to that of Example 43.

M.p.: 248-250 (dec.) ° C.

1H-NMR (400 MHz, DMSO-d6) δ: 1.76-1.86(1H, m), 2.06-2.14(1H, m),2.80(3H, s), 3.06-3.14(2H, m), 3.81(3H, s), 4.59(2H, d, J=6 Hz),7.08(1H, d, J=8.4 Hz), 7.34(1H, dd, J=8.4, 2.2 Hz), 7.44(1H, d, J=2.2Hz), 7.86-7.95(2H, m), 8.02(1H, d, J=8.8 Hz), 8.54(1H, d, J=2.0 Hz)

Example 456-Chloro-1-(4-ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)aminophthalazine

A mixture (4.83 g) comprising1,6-dichloro-4-(3,4-methylenedioxybenzyl)aminophthalazine and4,6-dichloro-1-(3,4-methylenedioxybenzyl)aminophthalazine was preparedfrom 1,4,6-trichlorophthalazine (3.38 g) prepared in Preparative Example7 and piperonylamine (2.21 g) in a similar manner to that of Example 1.The title compound (0.22 g) was prepared from 0.8 g of the mixture in asimilar manner to that of Example 3 as a less polar product.

1H-NMR (400 MHz, CDCl3) δ: 1.28(3H, t, J=7.0 Hz), 1.90-2.10(4H, m),2.46-2.55(1H, m), 2.96-3.05(2H, m), 3.53-3.60(2H, m), 4.16(2H, q, J=7.0Hz), 4.70(2H, d, J=5.0 Hz), 5.21(1H, t, J=5.0 Hz), 5.91(2H, s), 6.73(1H,d, J=8.0 Hz), 6.87(1H, dd, J=8.0, 1.5 Hz), 6.91(1H, d, J=1.5 Hz),7.68(1H, dd, J=8.5, 2.0 Hz), 7.78(1H, d, J=2.0 Hz), 7.96(1H, d, J=8.5Hz)

Example 466-Chloro-4-(4-ethoxycarbonylpiperidino)-1-(3,4-methylenedioxybenzyl)aminophthalazine

The title compound (0.21 g) was prepared by repeating the same procedureas that of Example 45 and recovering a more polar product.

1H-NMR (400 MHz, CDCl3) δ: 1.25(3H, t, J=7.0 Hz), 1.96-2.14(4H, m),2.48-2.57(1H, m), 3.09-3.13(2H, m), 3.54-3.61(2H, m), 4.18(2H, q, J=7.0Hz), 4.71(2H, d, J=5.0 Hz), 5.13(1H, t, J=5.0 Hz), 5.93(2H, s), 6.75(1H,d, J=8.0 Hz, 6.88(1H, dd, J=8.0, 1.5 Hz), 6.92(1H, d, J=1.5 Hz),7.65(1H, dd, J=9.0, 2.0 Hz), 7.71(1H, d, J=9.0 Hz), 7.97(1H, d, J=2.0Hz)

Example 471-(4-Carboxypiperidino)-6-chloro-4-(3,4-methylene-dioxybenzyl)aminophthalazine

In a similar manner to that of Example 43, the title compound wasprepared from the compound prepared in Example 45.

M.p.: 165-187° C.

MASS: 441 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.80-1.91(2H, m), 1.94-2.01(2H, m),2.43-2.52(1H, m), 2.86-2.94(2H, m), 3.40-3.50(2H, m), 4.61(2H, d, J=5.0Hz), 5.98(2H, s), 6.87(1H, d, J=8.0 Hz), 6.90(1H, dd, J=8.0, 1.0 Hz),7.00(1H, d, J=1.0 Hz), 7.95(1H, br d, J=9.0 Hz), 8.03(1H, d, J=9.0 Hz),9.58(1H, br s)

Example 484-(4-Carboxypiperidino)-6-chloro-1-(3,4-methylene-dioxybenzyl)aminophthalazine

In a similar manner to that of Example 43, the title compound wasprepared from the compound prepared in Example 46.

M.p.: 152-154° C.

MASS: 441 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.80-1.90(2H, m), 1.94-2.01(2H, m),2.41-2.50(1H, m), 2.85-2.92(2H, m), 3.35-3.43(2H, m), 4.62(2H, d, J=5.0Hz), 5.96(2H, s), 6.84(1H, d, J=8.0 Hz), 6.88(1H, dd, J=8.0, 1.5 Hz),6.97(1H, d, J=1.5 Hz), 7.89(1H, d, J=2.0 Hz), 7.96(1H, dd, J=9.0, 2.0Hz), 8.39(1H, d, J=9.0 Hz)

Example 49 1-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-nitrophthalazine

In a similar manner to that of Example 1, the title compound wasprepared from 1,4-dichloro-6-nitrophthalazine prepared in PreparativeExample 8.

M.p.: 217.0-217.5° C.

MASS: 379 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 3.90(3H, s), 4.83(2H, d, J=5.5 Hz), 5.73(1H,t, J=5.5 Hz), 6.91(1H, d, J=8.0 Hz), 7.35(1H, dd, J=8.0, 2.0 Hz),7.47(1H, d, J=2.0 Hz), 8.38(1H, d, J=9.0 Hz), 8.65(1H, dd, J=9.0, 2.0Hz), 8.73(1H, d, J=2.0 Hz)

Example 50 4-Chloro-1-(3-chloro-4-methoxybenzyl)amino-6-nitrophthalazine

In a similar manner to that of Example 2, the title compound wasprepared from 1,4-dichloro-6-nitrophthalazine prepared in PreparativeExample 8.

M.p.: 179-180.5° C.

MASS: 379 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 3.82(3H, s), 4.70(2H, d, J=5.6 Hz),7.10(1H, d, J=8.4 Hz), 7.35(1H, d, J=8.8 Hz), 7.47(1H, d, J=2.0 Hz),8.63(1H, t, J=5.6 Hz), 8.65(1H, d, J=8.8 Hz), 8.71(1H, d, J=2.4 Hz),8.75(1H, dd, J=8.8, 2.4 Hz)

Example 514-(3-Chloro-4-methoxybenzyl)amino-1-(4-hydroxy-piperidino)-6-nitrophthalazinehydrochloride

In a similar manner to that of Example 4, the title compound wasprepared from the compound prepared in Example 49.

M.p.: 245-246 (dec.) ° C.

MASS: 444 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.70(2H, m), 1.96(2H, m), 3.05(2H, m),3.48(2H, m), 3.77(1H, m), 3.86(3H, s), 4.78(2H, d, J=5.2 Hz), 7.17(1H,d, J=8.4 Hz), 7.48(1H, dd, J=8.4, 2.0 Hz), 7.63(1H, d. J=2.0 Hz),8.34(1H, d, J=9.2 Hz), 8.78(1H, dd, J=9.2, 2.0 Hz), 9.78(1H, d, J=2.0Hz), 10.59(1H, br s), 14.04(1H, br s)

Example 524-(3-Chloro-4-methoxybenzyl)amino-1-[4-(hydroxymethyl)piperidino]-6-nitrophthalazinehydrochloride

In a similar manner to that of Example 4, the title compound wasprepared from the compound prepared in Example 49.

M.p.: 232-233 (dec.) ° C.

MASS: 458 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.48(2H, m), 1.64(1H, m), 1.83(2H, m),2.90(2H, m), 3.37(2H, d, J=6.4 Hz), 3.61(2H, m), 3.85(3H, s), 4.77(2H,d, J=6.0 Hz), 7.17(1H, d, J=8.4 Hz), 7.48(1H, dd, J=8.4, 2.4 Hz),7.63(1H, d. J=2.4 Hz), 8.32(1H, d, J=9.2 Hz), 8.78(1H, dd, J=9.2, 2.0Hz), 9.77(1H, d, J=2.0 Hz), 10.56(1H, br s)

Example 534-(3-Chloro-4-methoxybenzyl)amino-1-[4-(2-hydroxyethyl)piperidino]-6-nitrophthalazinehydrochloride

In a similar manner to that of Example 4, the title compound wasprepared from the compound prepared in Example 49.

M.p.: 233-236 (dec.) ° C.

MASS: 472 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.42-1.53(4H, m), 1.66(1H1, m), 1.84(2H,m), 2.89(2H, m), 3.51(2H, t, J=6.6 Hz), 3.58(2H, m), 3.85(3H, s),4.76(2H, d, J=5.6 Hz), 7.17(1H, d, J=8.8 Hz), 7.47(1H, dd, J=8.8, 2.0Hz), 7.62(1H, d, J=2.0 Hz), 8.33(1H, d, J=8.8 Hz), 8.77(1H, dd, J=8.8,2.0 Hz), 9.74(1H, d, J=2.0 Hz), 10.45(1H, br s)

Example 544-(3-Chloro-4-methoxybenzyl)amino-1-[4-(2-hydroxyethyl)piperazin-1-yl]-6-nitrophthalazine

In a similar manner to that of Example 3, the title compound wasprepared from the compound prepared in Example 49.

M.p.: 199-200 (dec.) ° C.

MASS: 473 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 2.69(2H, t, J=5.4 Hz), 2.80(4H, br s),3.37(4H, br t), 3.70(2H, t, J=5.4 Hz), 3.90(3H, s), 4.79(2H, d, J=5.2Hz), 6.87(1H, t, J=5.2 Hz), 6.91(1H, d, J=8.4 Hz), 7.37(1H, dd, J=8.4,2.4 Hz), 7.50(1H, d, J=2.4 Hz), 8.16(1H, d, J=9.2 Hz), 8.51(1H, dd,J=9.2, 2.0 Hz), 9.13(1H, d, J=2.0 Hz)

Example 551-(4-Ethoxycarbonylpiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-nitrophthalazine

In a similar manner to that of Example 3, the title compound wasprepared from the compound prepared in Example 49.

M.p.: 208.5-209.5° C.

MASS: 500 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 1.30(3H, t, J=7.0 Hz), 2.01-2.15(4H, m),2.53-2.59(1H, m), 3.04-3.11(2H, m), 3.56-3.64(2H, m), 3.92(3H. s),4.20(2H, q, J=7.0 Hz), 4.79(2H, d, J=5.5 Hz), 5.23(1H, t, J=5.5 Hz),6.94(1H, d, J=8.5 Hz), 7.35(1H, dd, J=8.5, 2.0 Hz), 7.48(1H, d, J=2.0Hz), 8.20(1H, d, J=9.0 Hz), 8.55(1H, dd, J=9.0, 2.0 Hz), 8.65(1H, d,J=2.0 Hz)

Example 561-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-nitrophthalazinehydrochloride

1-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-nitrophthalazinewas prepared from the compound prepared in Example 55 in a similarmanner to that of Example 43 and further converted into the titlecompound in the same manner as that employed in Example 4 for theformation of hydrochloride.

M.p.: 137-143 (dec.) ° C.

MASS: 472 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.85-1.92(2H, m), 1.97-2.05(2H, m),2.50-2.60(1H, m), 2.96-3.03(2H, m), 3.52-3.56(2H, m), 3.86(3H, s),4.75(2H, d, J=4.5 Hz), 7.18(1H, d, J=8.5 Hz), 7.46(1H, m), 7.61(1H, d,J=2.0 Hz), 8.36(1H, d, J=9.0 Hz), 8.76(1H, dd, J=9.0, 2.0 Hz), 9.70(1H,m)

Example 57 1-Chloro-4-(3,4-methylenedioxybenzyl)amino-6-nitrophthalazine

In a similar manner to that of Example 1, the title compound wasprepared from 1,4-dichloro-6-nitrophthalazine prepared in PreparativeExample 8.

M.p.: 186.5-188.0° C.

MASS: 359 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 4.80(2H, d, J=5.0 Hz), 5.73(1H, t, J=5.0 Hz),5.95(2H, s), 6.78(1H, d, J=8.0 Hz), 6.92(1H, dd, J=8.0, 2.0 Hz),6.94(1H, d, J=2.0 Hz), 8.37(1H, d, J=9.0 Hz), 8.64(1H, dd, J=9.0, 2.0Hz), 8.73(1H, d, J=2.0 Hz)

Example 58 4-Chloro-1-(3,4-methylenedioxybenzyl)amino-6-nitrophthalazine

In a similar manner to that of Example 2, the title compound wasprepared from 1,4-dichloro-6-nitrophthalazine prepared in PreparativeExample 8.

M.p.: 240-242 (dec.) ° C.

MASS: 359 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 4.78(2H, d, J=5.0 Hz), 5.52(1H, t, J=5.0 Hz),5.96(2H, s), 6.78(1H, d, J=8.0 Hz), 6.91(1H, dd, J=8.0, 1.5 Hz),6.93(1H, d, J=1.5 Hz), 7.98(1H, d, J=9.0 Hz), 8.59(1H, dd, J=9.0, 2.0Hz), 9.05(1H, d, J=2.0 Hz)

Example 591-(4-Dimethylaminopiperidino)-4-(3,4-methylene-dioxybenzyl)amino-6-nitrophthalazine

In a similar manner to that of Example 3, the title compound wasprepared from1-chloro-4-(3,4-methylenedioxybenzyl)amino-6-nitrophthalazine preparedin Example 57.

M.p.: 105.0-107.0° C.

MASS: 451 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 1.79(2H, ddd, J=13.0, 13.0, 4.0 Hz), 2.04(2H,d, J=13.0 Hz), 2.31-2.40(1H, m), 2.38(6H, s), 3.03(2H, dt, J=13.5, 1.5Hz), 3.66(2H, d, J=13.5 Hz), 4.77(2H, d, J=5.0 Hz), 5.15(1H, t, J=5.0Hz), 5.98(2H, s), 6.82(1H, d, J=8.0 Hz), 6.94(1H, dd, J=8.0, 1.5 Hz),6.97(1H, d, J=1.5 Hz), 8.19(1H, d, J=9.0 Hz), 8.54(1H, dd, J=9.0, 2.0Hz), 8.63(1H, d, J=2.0 Hz)

Example 601-(Imidazol-1-yl)-4-(3,4-methylenedioxybenzyl)amino-6-nitrophthalazine

In a similar manner to that of Example 3, the title compound wasprepared from1-chloro-4-(3,4-methylenedioxybenzyl)amino-6-nitrophthalazine preparedin Example 57.

M.p.: 154.0-155.5° C.

MASS: 391 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 4.89(2H, d, J=5.5 Hz), 5.97(2H, s), 6.05(1H,t, J=5.5 Hz), 6.82(1H, d, J=8.0 Hz), 6.96(1H, dd, J=8.0, 2.0 Hz),6.98(1H, d, J=2.0 Hz), 7.35(1H, s), 7.44(1H, s), 7.99(1H, d, J=9.0 Hz),8.02(1H, s), 8.61(1H, dd, J=9.0, 2.0 Hz), 8.85(1H, d, J=2.0 Hz)

Example 611-(4-Ethoxycarbonylpiperidino)-4-(3,4-methylene-dioxybenzyl)amino-6-nitrophthalazine

In a similar manner to that of Example 3, the title compound wasprepared from the compound prepared in Example 57.

M.p.: 220-222° C.

MASS: 480 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 1.30(3H, t, J=7.0 Hz), 1.99-2.16(4H, m),2.52-2.60(1H, m), 3.03-3.11(2H, m), 3.57-3.63(2H, m), 4.20(2H. q, J=7.0Hz), 4.77(2H, d, J=5.0 Hz), 5.17(1H, t, J=5.0 Hz), 5.98(2H, s), 6.82(1H,d, J=8.0 Hz), 6.94(1H, dd, J=8.0, 1.5 Hz), 6.97(1H, d, J=1.5 Hz),8.20(1H, d, J=9.0 Hz), 8.54(1H, dd, J=9.0, 2.0 Hz), 8.64(1H, d, J=2.0Hz)

Example 62 Potassium salt of1-(4-carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-nitrophthalazine

Potassium hydroxide (0.5 g) was dissolved in 30 ml of 50% aqueousmethanol, followed by the addition of 0.26 g of the compound prepared inExample 61. The obtained mixture was stirred at room temperature for 4hours.

The solvent was distilled away in a vacuum and water was added to theresidue to form a solution. This solution was neutralized with dilutehydrochloric acid to precipitate a solid. This solid was recovered byfiltration and dissolved in an aqueous solution of potassium carbonate.The obtained solution was adsorbed on an octadecylsilanol column andeluted with water/methanol to conduct purification. The obtained solidwas crystallized from ethanol/ethyl acetate to give 0.15 g of the titlecompound as a pale-yellow solid.

M.p.: 206-209° C. (dec.)

1H-NMR (400 MHz, DMSO-d6) δ: 1.64-1.76(2H, m), 1.76-1.84(2H, m),1.84-1.92(1H, m), 2.65-2.73(2H, m), 3.26-3.32(2H, m), 4.53(2H, d, J=5.5Hz), 5.90(1H, t, J=5.5 Hz), 5.92(2H, s), 6.82(1H, d, J=8.0 Hz), 6.85(1H,dd, J=8.0, 1.0 Hz), 6.95(1H, d, J=1.0 Hz), 7.04(1H, d, J=2.0 Hz),7.09(1H, dd, J=9.0, 2.0 Hz), 7.64(1H, d, J=9.0 Hz)

Example 636-Amino-1-(4-ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)aminophthalazinehydrochloride

The compound (0.70 g) prepared in Example 61 was suspended in 50 ml ofethanol, followed by the addition of 50 ml of 10% palladium/carbon. Theobtained mixture was stirred in a hydrogen atmosphere of 1 atm overnightand filtered to remove the catalyst. The filtrate was concentrated in avacuum and the residue was dissolved in ethyl acetate. An excess of a 4Nsolution of hydrochloric acid in ethyl acetate was added to the obtainedsolution to form a hydrochloride. The solvent was distilled away in avacuum. The obtained residue was recrystallized from ethanol/diisopropylether to give 0.54 g of the title compound as a white powder.

M.p.: 156.5-158.5° C.

MASS: 450 (MH+)

1H-NMR (400 MHz, CD3OD) δ: 1.28(3H, t, J=7.0 Hz), 1.95-2.03(2H, m),2.04-2.12(2H, m), 2.57-2.65(1H, m), 2.99-3.11(2H, m), 3.60-3.68(2H, m),4.17(2H, q, J=7.0 Hz), 4.62(2H, s), 5.94(2H, s), 6.80(1H, d, J=8.0 Hz),6.89(1H, dd, J=8.0, 2.0 Hz), 6.92(1H, d, J=2.0 Hz), 7.29(1H, br s),7.31(1H, d, J=9.0 Hz), 7.90(1H, d, J=9.0 Hz)

Example 64 1-(3-Chloro-4-methoxybenzyl)amino-4,6,7-trichlorophthalazine

In a similar manner to that of Example 1, the title compound wasprepared from 1,4,6,7-tetrachlorophthalazine.

M.p.: 208-209° C.

MASS: 404 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 3.90(3H, s), 4.77(2H, d, J=5.0 Hz), 5.29(1H,t, J=5.0 Hz), 6.91(1H, d, J=8.0 Hz), 7.32(1H, dd, J=8.0, 2.0 Hz),7.45(1H, d, J=2.0 Hz), 7.89(1H, s), 8.28(1H, s)

Example 651-(3-Chloro-4-methoxybenzyl)amino-6,7-dichloro-4-(4-hydroxypiperidino)phthalazinehydrochloride

In a similar manner to that of Example 4, the title compound wasprepared from the compound prepared in Example 64.

M.p.: 174.0-175.5° C.

MASS: 467 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.63-1.73(2H, m), 1.91-1.99(2H, m),3.00-3.08(2H, m), 3.39-3.49(2H, m), 3.73-3.81(1H, m), 3.86(3H, s),4.71(2H, d, J=6.0 Hz), 7.14(1H, d, J=8.5 Hz), 7.45(1H, dd, J=8.5, 2.0Hz), 7.59(1H, d, J=2.0 Hz), 8.16(1H, s), 9.26(1H, s)

Example 661-(3-Chloro-4-methoxybenzyl)amino-6,7-dichloro-4-(4-ethoxycarbonylpiperidino)phthalazine

In a similar manner to that of Example 3, the title compound wasprepared from the compound prepared in Example 64.

1H-NMR (400 MHz, CDCl3) δ: 1.29(3H, t, J=7.0 Hz), 1.96-2.13(4H, m),2.48-2.55(1H, m), 3.98-3.05(2H, m), 3.53-3.58(2H, m), 3.86(3H, s),4.19(2H, q, J=7.0 Hz), 4.71(2H, d, J=5.0 Hz), 5.31(1H, t, J=5.0 Hz),6.84(1H, d, J=8.5 Hz), 7.27(1H, dd, J=8.5, 2.0 Hz), 7.40(1H, d, J=2.0Hz), 7.94(1H, s), 8.08(1H, s)

Example 671-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6,7-dichlorophthalazine

In a similar manner to that of Example 43, the title compound wasprepared from the compound prepared in Example 66.

M.p.: 268-273 (dec.) ° C.

MASS: 495 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.80-1.90(2H, m), 1.93-2.00(2H, m),2.40-2.50(1H, m), 3.84-3.91(2H, m), 3.30-3.45(2H, m), 3.82(3H, s),4.62(2H, d, J=5.5 Hz), 7.10(1H, d, J=8.5 Hz), 7.34(1H, dd, J=8.5, 2.0Hz), 7.44(1H, d, J=2.0 Hz), 7.85(1H, t, J=5.5 Hz), 8.05(1H, s), 8.68(1H,s)

Example 686-Chloro-1-(3-chloro-4-methoxybenzyl)amino-4-(3-pyridylmethyl)phthalazinedihydrochloride

In a similar manner to that of Example 4, the title compound wasprepared from the compound prepared in Preparative Example 11.

M.p.: 168.5-169.5° C.

MASS: 425 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 3.83(3H, s), 4.77(2H, s), 4.79(2H, s),7.13(1H, d, J=8.5 Hz), 7.47(1H, dd, J=8.5, 2.0 Hz), 7.62(1H, d, J=2.0Hz), 7.89(1H, dd, J=7.5, 5.5 Hz), 8.26(1H, dd, J=9.0, 2.0 Hz), 8.34(1H,d, J=7.5 Hz), 8.51(1H, d, J=2.0 Hz), 8.76(1H, d, J=5.5 Hz), 8.87(1H, s),9.12(1H, d, J=9.0 Hz), 11.01(1H, br s)

Example 696-Chloro-4-(3-chloro-4-methoxybenzyl)amino-1-(3-pyridylmethyl)phthalazinedihydrochloride

In a similar manner to that of Example 4, the title compound wasprepared from the compound prepared in Preparative Example 12.

M.p.: 170.0-171.0° C.

MASS: 425 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 3.85(3H, s), 4.78(2H, d, J=6.0 Hz),4.81(2H, s), 7.13(1H, d, J=8.5 Hz), 7.48(1H, dd, J=8.5, 2.0 Hz),7.62(1H, d, J=2.0 Hz), 7.95(1H, dd, J=8.0, 6.0 Hz), 8.25(1H, dd, J=8.5,2.0 Hz), 8.40-8.46(2H, m), 8.81(1H, d, J=6.0 Hz), 8.93(1H, d, J=1.0 Hz),9.26-9.31(1H, m), 10.91(1H, br s)

Example 704-(4-Ethoxycarbonylpiperidino)-1-(3,4-methylenedioxybenzyl)aminopyrido[3,4-d]pyridazine

The title compound was prepared in a similar manner to that of Example45.

M.p.: 135-136° C.

MASS: 436 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 1.30(3H, t, J=7.0 Hz), 2.00-2.16(4H, m),2.52-2.59(1H, m), 3.07-3.14(2H, m), 3.69-3.71(2H, m), 4.19(2H, q, J=7.0Hz), 4.74(2H, d, J=5.0 Hz), 5.00(1H, t, J=5.0 Hz), 5.96(2H, s), 6.80(1H,d, J=8.0 Hz), 6.91(1,H, dd, J=8.0, 1.5 Hz), 6.94(1H, d, J=1.5 Hz),7.48(1H, dd, J=5.5, 1.0 Hz), 8.93(1H, d, J=5.5 Hz), 9.42(1H, d, J=1.0Hz)

Example 711-(4-Ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)aminopyrido[3,4-d]pyridazine

The title compound was prepared in a similar manner to that of Example46.

M.p.: 119-120.5° C.

MASS: 436 (MH+)

1H-NMR (400 MHz, CDCl3) δ: 1.30(3H, t, J=7.0 Hz), 1.97-2.15(4H, m),2.51-2.59(1H, m), 3.01-3.08(2H, m), 3.61-3.67(2H, m), 4.19(2H, q, J=7.0Hz), 4.78(2H, d, J=5.0 Hz), 5.24(1H, t, J=5.0 Hz), 5.97(2H, s), 6.81(1H,d, J=8.0 Hz), 6.93(1H, dd, J=8.0, 1.5 Hz), 6.97(1H, d, J=1.5 Hz),7.75(1H, dd, J=5.5, 1.0 Hz), 8.93(1H, d, J=5.5 Hz), 9.21(1H, d, J=1.0Hz)

Example 724-(4-Carboxypiperidino)-1-(3,4-methylenedioxybenzyl)aminopyrido[3,4-d]pyridazine

In a similar manner to that of Example 43, the title compound wasprepared from the compound prepared in Example 70.

M.p.: 138-140° C.

MASS: 408 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.82-1.93(2H, m), 1.94-2.20(2H, m),2.45-2.52(1H, m), 2.89-2.98(2H, m), 3.46-3.55(2H, m), 4.62(2H, d, J=5.5Hz), 5.96(2H, s), 6.85(1H, d, J=8.0 Hz), 6.87(1H, dd, J=8.0, 1.0 Hz),6.97(1H, d, J=1.0 Hz), 7.88(1H, t, J=5.5 Hz), 8.17(1H, d, J=5.5 Hz),8.96(1H, d, J=5.5 Hz), 9.29 (1H, s), 12.25(1H, br s)

Example 731-(4-Carboxypiperidino)-4-(3,4-methylenedioxy-benzyl)aminopyrido[3,4-d]pyridazine

In a similar manner to that of Example 43, the title compound wasprepared from the compound prepared in Example 71.

M.p.: 205-206° C.

MASS: 408 (MH+)

1H-NMR (400 MHz, DMSO-d6) δ: 1.80-1.91(2H, m), 1.94-2.01(2H, m),2.42-2.50(1H, m), 2.84-2.92(2H, m), 3.42-3.48(2H, m), 4.64(2H, d, J=5.5Hz), 5.97(2H, s), 6.85(1H, d, J=8.0 Hz), 6.89(1H, dd, J=8.0, 1.5 Hz),6.99(1H, d, J=1.5 Hz), 7.76(1H, d, J=5.5 Hz), 8.05(1H, t, J=5.5 Hz),8.93(1H, d, J=5.5 Hz), 9.67(1H, s)

What is claimed is:
 1. A fused pyridazine compound represented by thegeneral formula (II) or a pharmacologically acceptable salt thereof:

wherein n represents 1 or 2; p represents 1, 2, or 3; R¹ represents ahalogen atom, a nitro group, an amino group, a cyano group or a4-hydroxypiperidin-1-yl group; R² and R³ represent each independently ahalogen atom, a lower alkyl group or a lower alkoxy group, or R² and R³may form a methylenedioxy ring together; the bond illustrated by thefollowing line: - - - represents a single bond or a double bond, and;(1) when the above bond is a double bond; then X represents a nitrogenatom, and Y represents a ═C—Z group, wherein Z is selected from thegroup consisting of: (i) a halogen atom, (ii) a group represented by thefollowing formula:

 wherein p represents 0 or 1, and m represents 0, 1 or 2, (iii) a grouprepresented by the following formula:

 wherein R⁴ represents a carbamoyl group, a carboxy group, a carboxylategroup with potassium atom, a lower alkoxycarbonyl group or adialkylamino group, (iv) a group represented by the following formula:

 wherein one of R⁵ or R⁶ represents a hydrogen atom and the otherrepresents a hydroxy group, (v) a group represented by the followingformula:

 wherein R⁷ represents a pyridyl group, a pyrimidyl group or a lowerhydroxyalkyl group, (vi) a group represented by the following formula:

 wherein the bond illustrated by the following line: - - - represents aeither single bond or a double bond, (vii) a hydroxypyrrolidinyl groupattached by way of the N atom; (viii) a hydroxymethylpyrrolidinyl groupattached by way of the N atom, (ix) an imidazolyl group, (x) amorpholinyl group attached by way of the N atom, (xi) a pyridylmethylgroup, (xii) a group represented by the following formula:

 wherein R⁸ represents a hydrogen atom or a lower alkyl group, R⁹represents a pyridyl group, a lower hydroxyalkyl group or a carboxyalkylgroup, (xiii) a lower alkoxy group, and (xiv) a lower, hydroxyalkoxygroup; (2) when the above bond is a single bond; then X represent a>NR¹⁰ group, wherein R¹⁰ represents a hydrogen atom, carboxymethylgroup, a lower alkoxycarbonylmethyl group, a tetrahydropyranylalkylgroup or a hydroxyalkyl group, and Y represents a carbonyl group, withthe proviso that compounds wherein n is 1, R¹ is a cyano group, R² andR³ represent each independently a halogen atom or methoxy group, thebond illustrated by the line - - - is a double bond, X is a nitrogenatom and Y is a ═C—Z group, where Z is a halogen atom or a grouprepresented by the formula

are excluded.
 2. The compound according to claim 1, wherein Z is ahydroxypyrrolidinyl group or a hydroxymethylpyrrolidinyl group.
 3. Afused pyridazine compound selected from the group consisting of1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine,4-chloro-1-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine,4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-oxo-1,4-dihydropyrid-1-yl)phthalazine,4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-[4-(hydroxymethyl)piperidino]phthalazinehydrochloride,4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(3-hydroxypropyl)aminophthalazine,4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-[4-(2-hydroxyethyl)piperidino]phthalazinehydrochloride,4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxy-4-methylpiperidino)phthalazinehydrochloride,4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(3-hydroxypiperidino)phthalazinehydrochloride,4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(2-pyridylmethyl)aminophthalazinedihydrochloride,4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-pyridylmethyl)aminophthalazinedihydrochloride,4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(3-pyridylmethyl)aminophthalazinedihydrochloride,4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-[N-(3-hydroxypropyl)-N-methylamino]phthalazine,4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-[4-(2-pyridyl)piperazin-1-yl]phthalazinedihydrochloride,4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-[4-(2-pyrimidyl)piperazin-1-yl]phthalazinedihydrochloride,1-(4-carbamoylpiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine,4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-[4-(2-hydroxyethyl)piperazin-1-yl]phthalazinedihydrochloride,4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-oxopiperidino)phthalazinehydrochloride,1-(4-carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)-amino-6-cyanophthalazinehydrochloride,4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1(2H)-phthalazinone,2-tert-butoxycarbonylmethyl-4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1(2H)-phthalazinone,2-carboxymethyl-4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1(2H)-phthalazinone,4-(3-chloro-4-methoxybenzyl)amino-6-cyano-2-[3-(tetrahydropyran-2-yloxy)propyl]-1(2H)-phthalazinone4-(3-chloro-4-methoxybenzyl)amino-6-cyano-2-(3-hydroxypropyl)-1(2H)-phthalazinone,6-cyano-1-(4-hydroxypiperidino)-4-(3,4-methylenedioxybenzyl)aminophthalazinehydrochloride, 4-(3-chloro-4-methoxybenzylamino-1,6-dichlorophthalazine,1-(3-chloro-4-methoxybenzyl)amino-4,6-dichlorophthalazine,6-chloro-4-(3-chloro-4-methoxybenzyl)amino-1-(3-hydroxypyrrolidino)phthalazine,(R)-6-chloro-4-(3-chloro-4-methoxybenzyl)amino-1-[2-(hydroxymethyl)pyrrolidino]phthalazinehydrochloride,6-chloro-4-(3-chloro-4-methoxybenzyl)amino-1-(imidazol-1-yl)phthalazine,6-chloro-4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxypiperidino)phthalazinehydrochloride,1,6-bis-(4-hydroxypiperidino)-4-(3-chloro-4-methoxybenzyl)aminophthalazine,6-chloro-4-(3-chloro-4-methoxybenzyl)amino-1-morpholinophthalazinehydrochloride, 6-chloro-4-(3-chloro-4-methoxybenzyl)amino-1-(3-hydroxypropyl)aminophthalazine,6-chloro-4-(3-chloro-4-methoxybenzyl)amino-1-[4-(hydroxymethyl)piperidino]phthalazine,6-chloro-4-(3-chloro-4-methoxybenzyl)amino-1-[4-(2-hydroxyethyl)piperidino]phthalazine,6-chloro-4-(3-chloro-4-methoxybenzyl)amino-1-ethoxyphthalazine,6-chloro-4-(3-chloro-4-methoxybenzyl)amino-1-(3-hydroxypropyloxy)phthalazine,6-chloro-4-(3-chloro-4-methoxybenzyl)amino-1-[N-(3-hydroxypropyl)-N-methylamino]phthalazine,6-chloro-4-(3-chloro-4-methoxybenzyl)amino-1-(4-oxopiperidino)phthalazinehydrochloride,6-chloro-4-(3-chloro-4-methoxybenzyl)amino-1-(4-ethoxycarbonylpiperidino)phthalazine,1-(4-carboxypiperidino)-6-chloro-4-(3-chloro-4-methoxybenzyl)aminophthalazine,1-[N-(3-carboxypropyl)-N-methylamino]-6-chloro-4-(3-chloro-4-methoxybenzyl)aminophthalazine,6-chloro-1-(4-ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)aminophthalazine,6-chloro-4-(4-ethoxycarbonylpiperidino)-1-(3,4-methylenedioxybenzyl)aminophthalazine,1-(4-carboxypiperidino)-6-chloro-4-(3,4-methylenedioxybenzyl)aminophthalazine,4-(4-carboxypiperidino)-6-chloro-1-(3,4-methylenedioxybenzyl)aminophthalazine,1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-nitrophthalazine,4-chloro-1-(3-chloro-4-methoxybenzyl)amino-6-nitrophthaline,4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxypiperidino)-6-nitrophthalazinehydrochloride,4-(3-chloro-4-methoxybenzyl)amino-1-[4-(hydroxymethyl)piperidino]-6-nitrophthalazinehydrochloride,4-(3-chloro-4-methoxybenzyl)amino-1-[4-(2-hydroxyethyl)piperidino]-6-nitrophthalazinehydrochloride,4-(3-chloro-4-methoxybenzyl)amino-1-[4-(2-hydroxyethyl)piperazin-1-yl]-6-nitrophthalazine,1-(4-ethoxycarbonylpiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-nitrophthalazine,1-(4-carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-nitrophthalazinehydrochloride,1-chloro-4-(3,4-methylenedioxybenzyl)amino-6-nitrophthalazine,4-chloro-1-(3,4-methylenedioxybenzyl)amino-6-nitrophthalazine,1-(4-dimethylaminopiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-nitrophthalazine,1-(imidazol-1-yl)-4-(3,4-methylenedioxybenzyl)amino-6-nitrophthalazine,1-(4-ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-nitrophthalazine,potassium salt of1-(4-carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-nitrophthalazine,6-amino-1-(4-ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)aminophthalazinehydrochloride,1-(3-chloro-4-methoxybenzyl)amino-4,6,7-trichlorophthalazine,1-(3-chloro-4-methoxybenzyl)amino-6,7-dichloro-4-(4-hydroxypiperidino)phthalazinehydrochloride,1-(3-chloro-4-methoxybenzyl)amino-6,7-dichloro-4-(4-ethoxycarbonylpiperidino)phthalazine,1-(4-carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6,7-dichlorophthalazine,6-chloro-1-(3-chloro-4-methoxybenzyl)amino-4-(3-pyridylmethyl)phthalazinedihydrochloride, and6-chloro-4-(3-chloro-4-methoxybenzyl)amino-1-(3-pyridylmethyl)phthalazinedihydrochloride.
 4. A pharmaceutical composition, comprising thecompound according to claim 1, and a pharmaceutically acceptable carriertherefor.
 5. A method for treating diseases for which an antiplateletaction is efficacious comprising administering an effective amount ofthe compound according to claim 1 to a patient in need thereof.
 6. Amethod for treating hypertension comprising administering an effectiveamount of the compound according to claim 1 to a patient in needthereof.